Indolecarboxylic acid derivative having pgd2 receptor antagonistic activity

ABSTRACT

The present invention provides an indolecarboxylic acid derivative having DP receptor antagonistic activity and a pharmaceutical composition comprising the said compound as an active ingredient, and further a therapeutic agent for treating allergic diseases.
         A compound of the general formula (I):       

     
       
         
         
             
             
         
       
         
         
           
             wherein the ring A is an aromatic carbocyclic ring etc.; the ring B is a nitrogen-containing non-aromatic heterocyclic ring etc.; the formula of —X 1 ═X 2 —X 3 ═X 4 — is a formula of —C(R 1 )═C(R 2 )—C(R 3 )═C(R 4 )— etc.; X 5  is C(R 5 ) or N; R 1 , R 2 , R 3 , R 4  and R 5  is independently a hydrogen atom, a halogen atom etc; R 6  is a formula of —Z—R 10  etc. wherein Z is alkylene etc., and R 10  is carboxy etc.; R 7  is optionally substituted alkyloxy etc.; R 8  is independently a halogen atom etc.; R 9  is independently optionally substituted alkyl etc.; Y is a single bond etc.; n is 0 etc.; q is 0 etc.; 
             a pharmaceutically acceptable salt or a solvate thereof.

TECHNICAL FIELD

This invention relates to an indolecarboxylic acid derivative having DPreceptor antagonistic activity and a medicinal use thereof.

BACKGROUND ART

Prostaglandin D2(PGD2) is a metabolic product of arachidonic acidthrough PGG2 and PGH2, and known to have various potent physiologicalactivities. For example, in non-patent literature 1 it is described thatPGD2 is involved in sleeping and secretion of hormones in centralnervous system, and in inhibiting activity of platelet aggregation,contraction of bronchial smooth muscle, vasodilation and constriction ofa blood vessel etc. in peripheral system. Moreover, PGD2 is consideredto be involved in forming pathological condition of an allergic diseasesuch as bronchial asthma since it is a major metabolic product ofarachidonic acid produced from a mast cell, and has a potentbronchoconstricting effect, causing an increase of vascular permeabilityand migration of inflammatory cell such as eosinophils.

A DP receptor (also called DP1 receptor) or CRTH2 receptor (also calledDP2 receptor) is known as a receptor of PGD2 but these are completelydifferent receptors. In Patent literatures 1-10 indole derivativeshaving a DP receptor antagonistic activity is disclosed, and in Patentliteratures 11-15 indole derivatives having a CRTH2receptor-antagonistic activity is disclosed

Also, indole derivatives having inhibitory activity against noradrenalinre-uptake are disclosed in Patent literature 16.

-   Patent literature 1: WO 2001/079169 Pamphlet-   Patent literature 2: WO 2002/094830 Pamphlet-   Patent literature 3: WO 2003/062200 Pamphlet-   Patent literature 4: WO 2004/039807 Pamphlet-   Patent literature 5: WO 2004/103970 Pamphlet-   Patent literature 6: WO 2004/111047 Pamphlet-   Patent literature 7: WO 2005/056527 Pamphlet-   Patent literature 8: WO 2003/022813 Pamphlet-   Patent literature 9: WO 2003/022814 Pamphlet-   Patent literature 10: WO 2004/078719 Pamphlet-   Patent literature 11: WO 2003/097598 Pamphlet-   Patent literature 12: WO 2003/066046 Pamphlet-   Patent literature 13: WO 2003/066047 Pamphlet-   Patent literature 14: WO 2005/040112 Pamphlet-   Patent literature 15: GB 2407318 Pamphlet-   Patent literature 16: WO 2005/019208 Pamphlet-   Non-patent literature 1: Pharmacol. Review, Vol. 46, page 205-229    (1994)-   Non-patent literature 2: Pharmaco., Vol. 55 (1), page 56-64 (2000)

DISCLOSURE OF INVENTION Problem to be Solved

The present invention provides an indolecarboxylic acid derivativehaving DP receptor antagonistic activity and a pharmaceuticalcomposition comprising the said compound as an active ingredient. Thesaid pharmaceutical composition is useful as a therapeutic agent fortreating allergic diseases.

Means for Solving Problem

The present inventors have found that the indolecarboxylic acidderivative shown below has a potent DP receptor antagonistic activity,and the pharmaceutical composition comprising the said compound as anactive ingredient is useful as a therapeutic agent for treating allergicdiseases.

The present invention relates to

1) a compound of the general formula (I):

wherein the ring A is an aromatic carbocyclic ring or an aromaticheterocyclic ring;

the ring B is a nitrogen-containing non-aromatic heterocyclic ring or anitrogen-containing aromatic heterocyclic ring;

X¹ is —N═ or —C(R¹)═;

X² is —N═ or —C(R²)═;

X³ is —N═ or —C(R³)═;

X⁴ is —N═ or —C(R⁴)═;

X⁵ is —N═ or —C(R⁵)═;

R¹, R², R³, R⁴, R⁵ and R⁶ are independently a hydrogen atom, a halogenatom, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkenyl, hydroxy, optionally substitutedalkyloxy, optionally substituted alkenyloxy, optionally substitutedalkynyloxy, optionally substituted cycloalkyloxy, optionally substitutedcycloalkenyloxy, mercapto, optionally substituted alkylthio, optionallysubstituted alkenylthio, optionally substituted alkynylthio, optionallysubstituted alkylsulfinyl, optionally substituted alkylsulfonyl,optionally substituted alkylsulfonyloxy, optionally substitutedcycloalkylthio, optionally substituted cycloalkylsulfinyl, optionallysubstituted cycloalkylsulfonyl, optionally substitutedcycloalkylsulfonyloxy, optionally substituted cycloalkenylthio,optionally substituted cycloalkenylsulfinyl, optionally substitutedcycloalkenylsulfonyl, optionally substituted cycloalkenylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted aryloxycarbonyl,optionally substituted carbamoyl, optionally substituted sulfamoyl,cyano, nitro, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted arylthio, optionally substitutedarylsulfinyl, optionally substituted arylsulfonyl, optionallysubstituted arylsulfonyloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroarylthio, optionally substituted heteroarylsulfinyl, optionallysubstituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, an optionally substituted non-aromaticheterocyclic group or a group of the formula: -L³-R¹⁰, wherein R¹⁰ ishydroxyalkyl, carboxy, alkyloxycarbonyl, optionally substitutedcarbamoyl or a carboxy equivalent, and L³ is a single bond, optionallysubstituted alkylene optionally containing one or two heteroatom(s),optionally substituted alkenylene optionally containing one or twoheteroatom(s), optionally substituted alkynylene optionally containingone or two heteroatom(s), an oxygen atom, a sulfur atom or —N(R¹¹)—,provided that at least one of R¹ to R⁶ is a group of -L³-R¹⁰;

R⁷ is a hydrogen atom, optionally substituted alkyloxy, optionallysubstituted alkenyloxy, optionally substituted alkynyloxy, optionallysubstituted cycloalkyloxy, optionally substituted cycloalkenyloxy,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted alkylthio, optionally substituted alkenylthio,optionally substituted alkynylthio, optionally substitutedcycloalkylthio, optionally substituted cycloalkenylthio, optionallysubstituted arylthio or optionally substituted heteroarylthio;

R⁸ is independently a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted cycloalkenyl,hydroxy, optionally substituted alkyloxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, optionally substitutedcycloalkyloxy, optionally substituted cycloalkenyloxy, mercapto,optionally substituted alkylthio, optionally substituted alkenylthio,optionally substituted alkynylthio, optionally substitutedalkylsulfinyl, optionally substituted alkylsulfonyl, optionallysubstituted alkylsulfonyloxy, optionally substituted cycloalkylthio,optionally substituted cycloalkylsulfinyl, optionally substitutedcycloalkylsulfonyl, optionally substituted cycloalkylsulfonyloxy,optionally substituted cycloalkenylthio, optionally substitutedcycloalkenylsulfinyl, optionally substituted cycloalkenyl sulfonyl,optionally substituted cycloalkenylsulfonyloxy, optionally substitutedamino, acyl, optionally substituted alkyloxycarbonyl, optionallysubstituted alkenyloxycarbonyl, optionally substitutedalkynyloxycarbonyl, optionally substituted aryloxycarbonyl, optionallysubstituted carbamoyl, optionally substituted sulfamoyl, cyano, nitro,optionally substituted aryl, optionally substituted aryloxy, optionallysubstituted arylthio, optionally substituted arylsulfinyl, optionallysubstituted arylsulfonyl, optionally substituted arylsulfonyloxy,optionally substituted heteroaryl, optionally substituted heteroaryloxy,optionally substituted heteroarylthio, optionally substitutedheteroarylsulfinyl, optionally substituted heteroarylsulfonyl,optionally substituted heteroarylsulfonyloxy or an optionallysubstituted non-aromatic heterocyclic group;

R⁹ is independently a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted alkyloxy, oxo,optionally substituted aryl, optionally substituted heteroaryl or anoptionally substituted non-aromatic heterocyclic group;

M is carbonyl or sulfonyl;

Y is a single bond, optionally substituted alkylene optionallycontaining one or two heteroatom(s), optionally substituted alkenyleneoptionally containing one or two heteroatom(s), optionally substitutedalkynylene optionally containing one or two heteroatom(s), an oxygenatom, a sulfur atom or —N(R¹¹)—;

L¹ and L² are independently a single bond, optionally substitutedalkylene optionally containing one or two heteroatom(s), optionallysubstituted alkenylene optionally containing one or two heteroatom(s),optionally substituted alkynylene optionally containing one or twoheteroatom(s), or —N(R¹¹)—;

R¹¹ and R¹² are independently a hydrogen atoms, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, acyl, optionally substitutedalkyloxy, optionally substituted aryl, optionally substituted heteroarylor an optionally substituted non-aromatic heterocyclic group;

n is 0, 1 or 2; and

q is 0, 1, 2 or 3, provided that R⁷ is not a hydrogen atom when the ringB is an imidazoline ring and all of Y, L¹ and L² are single bonds;

a pharmaceutically acceptable salt or solvate thereof,

2) a compound of 1) wherein the formula of —X¹═X²—X³═X⁴— is—C(R¹)═C(R²)—C(R³)═C(R⁴)—, —N═C(R²)—C(R³)═C(R⁴)—, —C(R¹)═N—C(R³)═C(R⁴)—,—C(R¹)═C(R²)—N═C(R⁴)— or —C(R¹)═C(R²)—C(R³)═N—;

a pharmaceutically acceptable salt or solvate thereof,

3) a compound of 1) or 2) wherein R¹ is a group of the formula:

-L³-R¹⁰;

a pharmaceutically acceptable salt or solvate thereof,

4) a compound of 1) or 2) wherein R² is a group of the formula:

-L³-R¹⁰;

a pharmaceutically acceptable salt or solvate thereof,

5) a compound of 1) or 2) wherein R³ is a group of the formula:

-L³-R¹⁰;

a pharmaceutically acceptable salt or solvate thereof,

6) a compound of 1) or 2) wherein R⁴ is a group of the formula:

-L³-R¹⁰;

a pharmaceutically acceptable salt or solvate thereof,

7) a compound of 1) or 2) wherein R⁵ is a group of the formula:

—C(-L³-R¹⁰)═;

a pharmaceutically acceptable salt or solvate thereof,

8) a compound of 1) or 2) wherein R⁶ is a group of the formula:

-L³-R¹⁰;

a pharmaceutically acceptable salt or solvate thereof,

9) a compound of any of 1) to 6) or 8) wherein R⁵ is —N═ or —CH═;

a pharmaceutically acceptable salt or solvate thereof,

10) a compound of any of 1) to 9) wherein R¹⁰ is carboxy and L³ isoptionally substituted alkylene;

a pharmaceutically acceptable salt or solvate thereof,

11) a compound of any of 1) to 10) wherein the ring B is a formula of

and n is 0; a pharmaceutically acceptable salt or solvate thereof,12) a compound of any of 1) to 11) wherein the ring A is a benzene ringor a pyridine ring; a pharmaceutically acceptable salt or solvatethereof,13) a compound of any of 1) to 12) wherein R⁷ is optionally substitutedalkyloxy or optionally substituted alkylthio; a pharmaceuticallyacceptable salt or solvate thereof,14) a compound of any of 1) to 13) wherein R⁸ is a halogen atom,optionally substituted alkyl or optionally substituted alkyloxy, and qis 0 or 1; a pharmaceutically acceptable salt or solvate thereof,15) a compound of any of 1) to 14) wherein Y is a single bond and n is0; a pharmaceutically acceptable salt or solvate thereof,16) a compound of any of 1) to 15) wherein M is sulfonyl, L¹ is a singlebond and L² is a single bond; a pharmaceutically acceptable salt orsolvate thereof,17) a compound of the general formula (II):

wherein the ring C is a formula of

X⁵ is —N═ or —C(R⁵)═;

R¹, R², R³, R⁴ and R⁵ are independently hydrogen atoms, a halogen atom,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, hydroxy, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted cycloalkyloxy, optionally substitutedcycloalkenyloxy, mercapto, optionally substituted alkylthio, optionallysubstituted alkenylthio, optionally substituted alkynylthio, optionallysubstituted alkylsulfinyl, optionally substituted alkylsulfonyl,optionally substituted alkylsulfonyloxy, optionally substitutedcycloalkylthio, optionally substituted cycloalkylsulfinyl, optionallysubstituted cycloalkylsulfonyl, optionally substitutedcycloalkylsulfonyloxy, optionally substituted cycloalkenylthio,optionally substituted cycloalkenylsulfinyl, optionally substitutedcycloalkenylsulfonyl, optionally substituted cycloalkenylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted aryloxycarbonyl,optionally substituted carbamoyl, optionally substituted sulfamoyl,cyano, nitro, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted arylthio, optionally substitutedarylsulfinyl, optionally substituted arylsulfonyl, optionallysubstituted arylsulfonyloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroarylthio, optionally substituted heteroarylsulfinyl, optionallysubstituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy or an optionally substituted non-aromaticheterocyclic group;

R⁹ is independently a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted alkyloxy, oxo,optionally substituted aryl, optionally substituted heteroaryl or anoptionally substituted non-aromatic heterocyclic group;

R¹⁰ is hydroxyalkyl, carboxy, alkyloxycarbonyl, optionally substitutedcarbamoyl or a carboxy equivalent;

R¹³ is optionally substituted C1-C6 alkyloxy, optionally substitutedC2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionallysubstituted C1-C6 alkylthio, optionally substituted C2-C6 alkenylthio,optionally substituted C2-C6 alkynylthio, optionally substituted C3-C6cycloalkyloxy, optionally substituted C3-C6 cycloalkylthio, optionallysubstituted aryloxy or optionally substituted arylthio,

R¹⁴ is independently halogen atom, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted amino, acyl,optionally substituted alkyloxycarbonyl, optionally substitutedcarbamoyl, optionally substituted sulfamoyl, cyano, nitro, optionallysubstituted aryl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl or an optionally substituted non-aromaticheterocyclic group;

M is carbonyl or sulfonyl;

Z is CH, C(R¹⁴), or N;

L³ is a single bond, optionally substituted alkylene optionallycontaining one or two heteroatom(s), optionally substituted alkenyleneoptionally containing one or two heteroatom(s), optionally substitutedalkynylene optionally containing one or two heteroatom(s), an oxygenatom, a sulfur atom or a group of —N(R¹¹)—;

n is 0, 1 or 2; and

q is 0, 1, 2 or 3;

a pharmaceutically acceptable salt or solvate thereof,

18) a compound of 17) wherein M is sulfonyl;

a pharmaceutically acceptable salt or solvate thereof,

19) a compound of 17) or 18) wherein R¹⁰ is carboxy;

a pharmaceutically acceptable salt or solvate thereof,

20) a compound of any of 17) to 19) wherein X⁵ is —N═ or CH═;

a pharmaceutically acceptable salt or solvate thereof,

21) a compound of any of 17) to 20) wherein L³ is optionally substitutedalkylene;

a pharmaceutically acceptable salt or solvate thereof,

22) a compound of any of 17) to 21) wherein R⁵ is a hydrogen atom, ahalogen atom or alkyl;

a pharmaceutically acceptable salt or solvate thereof,

23) a compound of any of 17) to 22) wherein one of R¹ to R⁴ is ahydrogen atom, a halogen atom, optionally substituted alkyl, optionallysubstituted alkyloxy, optionally substituted amino, optionallysubstituted carbamoyl, optionally substituted aryl, optionallysubstituted heteroaryl or an optionally substituted non-aromaticheterocyclic group, and others of R¹ to R⁴ are a hydrogen atom, ahalogen atom or optionally substituted alkyl;

a pharmaceutically acceptable salt or solvate thereof,

24) a compound of any of 17) to 23) wherein R¹³ is optionallysubstituted C1-C6 alkyloxy or optionally substituted C1-C6 alkylthio;

a pharmaceutically acceptable salt or solvate thereof,

25) a compound of any of 17) to 24) wherein R¹⁴ is a halogen atom,optionally substituted alkyl or optionally substituted alkyloxy;

a pharmaceutically acceptable salt or solvate thereof,

26) a compound of any of 17) to 25) wherein R⁹ is alkyl or oxo, and n is0 or 1;

a pharmaceutically acceptable salt or solvate thereof,

27) a pharmaceutical composition comprising the compound of any of 1) to26), pharmaceutically acceptable salt or solvate thereof as an activeingredient,28) a pharmaceutical composition of 27) which is a DP receptorantagonist,29) a pharmaceutical composition of 27) which is a therapeutic agent forallergy,30) a pharmaceutical composition of 28) wherein the therapeutic agentfor allergy is a medicine for asthma,31) a method for treating a disease related to DP receptor characterizedby administration of the compound of any of 1) to 26), pharmaceuticallyacceptable salt or solvate thereof,32) a method of 31) wherein the disease related to DP receptor isasthma,33) use of the compound of any of 1) to 26), pharmaceutically acceptablesalt or solvate thereof, in the manufacturing of a therapeutic agent fortreating diseases related to DP receptor, and34) use of the compound of 33), pharmaceutically acceptable salt orsolvate thereof wherein the disease related to DP receptor is asthma,

The present invention also includes the following inventions;

(1) a compound of the general formula (I-a):

wherein the ring A^(a) is an aromatic carbocyclic ring or an aromaticheterocyclic ring;

the ring B^(a) is a 4- to 8-membered nitrogen-containing heterocyclicring containing one or two nitrogen atom(s);

X^(1a) is —N═ or —C(R^(1a))═;

X^(2a) is —N═ or —C(R^(2a))═;

X^(3a) is —N═ or —C(R^(3a))═;

X^(4a) is —N═ or —C(R^(4a))═;

R^(1a), R^(2a), R^(3a) and R^(4a) are independently a hydrogen atom, ahalogen atom, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcycloalkyl, optionally substituted alkyloxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, optionally substitutedalkylthio, optionally substituted alkenylthio, optionally substitutedalkynylthio, optionally substituted alkylsulfinyl, optionallysubstituted alkylsulfonyl, optionally substituted alkylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted carbamoyl, cyano,nitro, optionally substituted aryl, optionally substituted aryloxy,optionally substituted arylthio, optionally substituted arylsulfinyl,optionally substituted arylsulfonyl, optionally substitutedarylsulfonyloxy, optionally substituted heteroaryl, an optionallysubstituted heteroaryloxy, optionally substituted heteroarylthio,optionally substituted heteroarylsulfinyl, optionally substitutedheteroarylsulfonyl, optionally substituted heteroarylsulfonyloxy, anoptionally substituted non-aromatic heterocyclic group or a group of theformula: —Z^(a)—R^(10a), wherein R^(10a) is hydroxyalkyl, carboxy,alkyloxycarbonyl, optionally substituted carbamoyl or optionallysubstituted tetrazolyl, and Z is a single bond, alkylene, alkenylene,alkynylene, —O-alkylene or —S-alkylene;

R^(5a) and R^(6a) are independently a hydrogen atom, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl or a group of the formula: —Z^(a)—R^(10a), wherein R^(10a) ishydroxyalkyl, carboxy, alkyloxycarbonyl, optionally substitutedcarbamoyl or optionally substituted tetrazolyl, and Z^(a) is a singlebond, alkylene, alkenylene, alkynylene, —O-alkylene or —S-alkylene,provided that at least one of R^(1a) to R^(6a) is a group of theformula: —Z^(a)—R^(10a).

R^(7a) is optionally substituted alkyloxy, optionally substitutedalkylthio, optionally substituted cycloalkyloxy, optionally substitutedcycloalkylthio, optionally substituted aryloxy, optionally substitutedarylthio, optionally substituted heteroaryloxy or optionally substitutedheteroarylthio;

R^(8a) is independently a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted alkylthio, optionally substituted alkenylthio,optionally substituted alkynylthio, optionally substitutedalkylsulfinyl, optionally substituted alkylsulfonyl, optionallysubstituted alkylsulfonyloxy, optionally substituted amino, acyl,optionally substituted alkyloxycarbonyl, optionally substitutedalkenyloxycarbonyl, optionally substituted alkynyloxycarbonyl,optionally substituted carbamoyl, cyano, nitro, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylthio,optionally substituted arylsulfinyl, optionally substitutedarylsulfonyl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy, optionallysubstituted heteroarylthio, optionally substituted heteroarylsulfinyl,optionally substituted hetero aryl sulfonyl, optionally substitutedheteroarylsulfonyloxy or an optionally substituted non-aromaticheterocyclic group;

R^(9a) is independently optionally substituted alkyl or optionallysubstituted aryl;

Y^(a) is a single bond, alkylene, alkenylene or alkynylene;

ma is 0, 1 or 2;

na is 0, 1 or 2; and

pa is 0 or 1;

a pharmaceutically acceptable salt or solvate thereof,

(2) a compound of (1) wherein R^(6a) is a group of the formula:—Z^(a)—R^(10a), and R^(1a) to R^(5a) are not groups of the formula:—Z^(a)—R^(10a);

a pharmaceutically acceptable salt or hydrate thereof,

(3) a compound of (1) wherein R^(5a) is a group of the formula:—Z^(a)—R^(10a), and R^(1a), to R^(4a) and R^(6a) are not groups of theformula: —Z^(a)—R^(10a);

a pharmaceutically acceptable salt or hydrate thereof,

(4) a compound of (1) wherein R^(1a) is a group of the formula:—Z^(a)—R^(10a), and R^(2a) to R^(6a) are not groups of the formula:—Z^(a)—R^(10a);

a pharmaceutically acceptable salt or hydrate thereof,

(5) a compound of any of (1) to (4) wherein the ring B^(a) is a formulaof

and na is 0; a pharmaceutically acceptable salt or hydrate thereof,(6) a compound of any of (1) to (5) wherein the ring A^(a) is a benzenering or a pyridine ring; a pharmaceutically acceptable salt or hydratethereof,(7) a compound of any of (1) to (6) wherein pa is 1; a pharmaceuticallyacceptable salt or hydrate thereof,(8) a compound of any of (1) to (7) wherein Ya is a single bond; apharmaceutically acceptable salt or hydrate thereof,(9) a compound of any of (1) to (8) wherein R¹⁰ is carboxy; apharmaceutically acceptable salt or hydrate thereof,(10) a compound of any of (1) to (9) wherein—X^(1a)═X^(2a)—X^(3a)═X^(4a)— is—C(R^(1a))═C(R^(2a))—C(R^(3a))═C(R^(4a))—,—N═C(R^(2a))—C(R^(3a))═C(R^(4a))—, —C(R^(1a))═N—C(R^(3a))═C(R^(4a))—,—C(R^(1a))═C(R^(2a))—N═C(R^(4a))— or —C(R^(1a))═C(R^(2a))—C(R^(3a))═N—;

a pharmaceutically acceptable salt or hydrate thereof,

(11) a compound of the formula (II-a):

wherein the ring A^(a) is an aromatic carbocyclic ring or an aromaticheterocyclic ring;

the ring B^(a) is a 4- to 8-membered nitrogen-containing heterocyclicring containing one or two nitrogen atom(s);

R^(11a), R^(12a), R^(13a) and R^(14a) are independently a hydrogen atom,a halogen atom, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcycloalkyl, optionally substituted alkyloxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, optionally substitutedalkylthio, optionally substituted alkenylthio, optionally substitutedalkynylthio, optionally substituted alkylsulfinyl, optionallysubstituted alkylsulfonyl, optionally substituted alkylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted carbamoyl, cyano,nitro, optionally substituted aryl, optionally substituted aryloxy,optionally substituted arylthio, optionally substituted arylsulfinyl,optionally substituted arylsulfonyl, optionally substitutedarylsulfonyloxy, optionally substituted heteroaryl, an optionallysubstituted heteroaryloxy, optionally substituted heteroarylthio,optionally substituted heteroarylsulfinyl, optionally substitutedheteroarylsulfonyl, optionally substituted heteroarylsulfonyloxy or anoptionally substituted non-aromatic heterocyclic group;

R^(5a) is a hydrogen atom, optionally substituted alkyl, optionallysubstituted aryl or optionally substituted heteroaryl;

R^(7a) is optionally substituted alkyloxy, optionally substitutedalkylthio, optionally substituted cycloalkyloxy, optionally substitutedcycloalkylthio, optionally substituted aryloxy, optionally substitutedarylthio, optionally substituted heteroaryloxy or optionally substitutedheteroarylthio;

R^(8a) is independently a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted alkylthio, optionally substituted alkenylthio,optionally substituted alkynylthio, optionally substitutedalkylsulfinyl, optionally substituted alkylsulfonyl, optionallysubstituted alkylsulfonyloxy, optionally substituted amino, acyl,optionally substituted alkyloxycarbonyl, optionally substitutedalkenyloxycarbonyl, optionally substituted alkynyloxycarbonyl,optionally substituted carbamoyl, cyano, nitro, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylthio,optionally substituted arylsulfinyl, optionally substitutedarylsulfonyl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy, optionallysubstituted heteroarylthio, optionally substituted heteroarylsulfinyl,optionally substituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy or an optionally substituted non-aromaticheterocyclic group;

R^(9a) is independently optionally substituted alkyl or optionallysubstituted aryl;

R^(10a) is hydroxyalkyl, carbxy, alkyloxycarbonyl, optionallysubstituted carbamoyl or optionally substituted tetrazolyl;

Z^(a) is a single bond, alkylene, alkenylene, alkynylene, —O-alkylene or—S-alkylene;

ma is 0, 1 or 2;

na is 0, 1 or 2 and

pa is 0 or 1;

a pharmaceutically acceptable salt or hydrate thereof,

(12) a compound of (11) wherein the ring B^(a) is a ring of the formulaof

and na is 0;

a pharmaceutically acceptable salt or hydrate thereof,

(13) a compound of (11) or (12) wherein the ring A^(a) is a benzene ringor a pyridine ring; a pharmaceutically acceptable salt or hydratethereof,(14) a compound of any of (11) to (13) wherein pa is 1; apharmaceutically acceptable salt or hydrate thereof,(15) a compound of any of (11) to (14) wherein R^(10a) is carboxy; apharmaceutically acceptable salt or hydrate thereof,(16) a pharmaceutical composition comprising the compound of any of (1)to (15), pharmaceutically acceptable salt or hydrate thereof as anactive ingredient,(17) a pharmaceutical composition of (16) which has a PGD2 receptorantagonistic activity,(18) a pharmaceutical composition of (16) which is a therapeutic agentfor allergy,(19) a pharmaceutical composition of (16) which is a therapeutic agentfor asthma,(20) a method for treating a disease related to DP receptorcharacterized by administration of the compound of any of (1) to (15),pharmaceutically acceptable salt or hydrate thereof,(21) a method of (20) wherein the disease related to DP receptor isasthma,(22) use of the compound of any of (1) to (15), pharmaceuticallyacceptable salt or hydrate thereof, in the manufacturing of atherapeutic agent for treating diseases related to DP receptor, and(23) use of the compound of (22), pharmaceutically acceptable salt orhydrate thereof wherein the disease related to DP receptor is asthma.

Terms herein used are explained below. In the present specification eachterm is used under the unified definition and has the same meaning whenused alone or in combination with other terms.

In the present specification, a term of “halogen atom” means a fluorineatom, a chlorine atom, a bromine atom and an iodine atom. A fluorineatom, a chlorine atom and a bromine atom are preferable.

In the present specification, a term of “hetero atom” means an oxygenatom, a sulfur atom and a nitrogen atom.

In the present specification, a term of “alkyl” includes a monovalentstraight or branched hydrocarbon group having one to eight carbonatom(s). For example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl,n-hexyl, isohexyl, n-heptyl, n-octyl and the like are exemplified. C1-C6alkyl is preferred. C1-C4 alkyl is further preferred. When a number ofcarbon is specified, it means “alkyl” having the carbon number withinthe range.

In the present specification, a term of “alkenyl” includes a monovalentstraight or branched hydrocarbon group having two to eight carbon atomsand one or more double bond(s). For example, vinyl, allyl, 1-propenyl,2-butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl and the like areexemplified. C2-C6 alkenyl is preferred. Moreover, C2-C4 alkenyl isfurther preferred.

In the present specification, a term of “alkynyl” includes a monovalentstraight or branched hydrocarbon group having two to eight carbon atomsand one or more triple bond(s). For example, ethynyl, 1-propynyl,2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl, 2-heptynyl, 2-octynyl andthe like are exemplified. C2-C6 alkynyl is preferred. Moreover, C2-C4alkynyl is further preferred.

In the present specification, a term of “cycloalkyl” includes acycloalkyl having three to eight carbon atoms and for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and the like are exemplified. C3-C6 cycloalkyl is preferred.

In the present specification, a term of “cycloalkenyl” includes acycloalkenyl having three to eight carbon atoms and for example,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cycloocentyl and the like are exemplified. C3-C6 cycloalkenyl ispreferred.

In the present specification, a term of “alkyloxy” includes a groupwherein an oxygen atom is substituted with one “alkyl” above and forexample, methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy,isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy,2-pentyloxy, 3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy,3-hexyloxy, n-heptyloxy, n-octyloxy, and the like are exemplified. C1-C6alkyloxy is preferred. Moreover, C1-C4 alkyloxy is further preferred.When a number of carbon is specified, it means “alkyloxy” having thecarbon number within the range.

In the present specification, a term of “alkenyloxy” includes a groupwherein an oxygen atom is substituted with one “alkenyl” above and forexample, vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy,2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like are exemplified.C2-C6 alkenyloxy is preferred. Moreover, C2-C4 alkenyloxy is furtherpreferred. When a number of carbon is specified, it means “alkenyloxy”having the carbon number within the range.

In the present specification, a term of “alkynyloxy” includes a groupwherein an oxygen atom is substituted with one “alkynyl” above and forexample, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy,2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the likeare exemplified. C2-C6 alkynyloxy is preferred. Moreover, C2-C4alkynyloxy is further preferred. When a number of carbon is specified,it means “alkynyloxy” having the carbon number within the range.

In the present specification, a term of “cycloalkyloxy” includes a groupwherein an oxygen atom is substituted with one “cycloalkyl” above andfor example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy are exemplified. C3-C6cycloalkyloxy is preferred. When a number of carbon is specified, itmeans “cycloalkyloxy” having the carbon number within the range.

In the present specification, a term of “cycloalkenyloxy” includes agroup wherein an oxygen atom is substituted with one “cycloalkenyl”above and for example, cyclopropenyloxy, cyclobutenyloxy,cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy and cyclooctenyloxyare exemplified. C3-C6 cycloalkenyloxy is preferred. When a number ofcarbon is specified, it means “cycloalkenyloxy” having the carbon numberwithin the range.

In the present specification, a term of “alkylthio” includes a groupwherein a sulfur atom is substituted with one “alkyl” above, and forexample, methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio,isopentylthio, 2-pentylthio, 3-pentylthio, n-hexylthio, isohexylthio,2-hexylthio, 3-hexylthio, n-heptylthio, n-octylthio, and the like areexemplified. C1-C6 Alkylthio is preferred. Moreover, C1-C4 alkylthio isfurther preferred. When a number of carbon is specified, it means“alkylthio” having the carbon number within the range.

In the present specification, a term of “alkenylthio” includes a groupwherein a sulfur atom is substituted with one “alkenyl” above, and forexample, vinylthio, allylthio, 1-propenylthio, 2-butenylthio,2-pentenylthio, 2-hexenylthio, 2-heptenylthio, 2-octenylthio and thelike are exemplified. C2-C6 Alkenylthio is preferred. Moreover, C2-C4alkylthio is further preferred. When a number of carbon is specified, itmeans “alkenylthio” having the carbon number within the range.

In the present specification, a term of “alkynylthio” includes a groupwherein a sulfur atom is substituted with one “alkynyl” above and forexample, ethynylthio, 1-propynylthio, 2-propynylthio, 2-butynylthio,2-pentynylthio, 2-hexynylthio, 2-heptynylthio, 2-octynylthio and thelike are exemplified. C2-C6 alkynylthio is preferred. Moreover, C2-C4alkynylthio is further preferred. When a number of carbon is specified,it means “alkynylthio” having the carbon number within the range.

In the present specification, a term of “alkylsulfinyl” includes a groupwherein sulfinyl is substituted with one “alkyl” above and for example,methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl,n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl,tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl,2-pentylsulfinyl, 3-pentylsulfinyl, n-hexylsulfinyl, isohexylsulfinyl,2-hexylsulfinyl, 3-hexylsulfinyl, n-heptylsulfinyl, n-octylsulfinyl andthe like are exemplified. C1-C6 alkylsulfinyl is preferred. Moreover,C1-C4 alkylsulfinyl is further preferred.

In the present specification, a term of “alkylsulfonyl” includes a groupwherein sulfonyl is substituted with one “alkyl” above and for example,methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl,n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl,2-pentylsulfonyl, 3-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl,2-hexylsulfonyl, 3-hexylsulfonyl, n-heptylsulfonyl, n-octylsulfonyl andthe like are exemplified. C1-C6 alkylsulfonyl is preferred. Moreover,C1-C4 alkylsulfonyl is further preferred.

In the present specification, a term of “alkylsulfonyloxy” includes agroup wherein an oxygen atom is substituted with one “alkylsulfonyl”above and for example, methylsulfonyloxy, ethylsulfonyloxy,n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy,isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy,n-pentylsulfonyloxy, isopentylsulfonyloxy, 2-pentylsulfonyloxy,3-pentylsulfonyloxy, n-hexylsulfonyloxy, isohexylsulfonyloxy,2-hexylsulfonyloxy, 3-hexylsulfonyloxy, n-heptylsulfonyloxy,n-octylsulfonyloxy and the like are exemplified. C1-C6 alkylsulfonyl ispreferred. Moreover, C1-C4 alkylsulfonyl is further preferred.

In the present specification, a term of “cycloalkylthio” includes agroup wherein a sulfur atom is substituted with one “cycloalkyl” aboveand for example, cyclopropylthio, cyclobutylthio, cyclopentylthio,cyclohexylthio, cycloheptylthio, cyclooctylthio and the like areexemplified. C3-C6 cycloalkylthio is preferred. When a number of carbonis specified, it means “cycloalkylthio” having the carbon number withinthe range.

In the present specification, a term of “cycloalkylsulfinyl” includes agroup in which sulfinyl is substituted with one “cycloalkyl” above. Forexample, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl,cyclohexylsulfinyl, cycloheptylsulfinyl, and cyclooctylsulfinyl areexemplified. Preferably C3-C6 cycloalkylsulfinyl is exemplified.

In the present specification, a term of “cycloalkylsulfonyl” includes agroup in which sulfonyl is substituted with one “cycloalkyl” above. Forexample, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl,cyclohexylsulfonyl, cycloheptylsulfonyl, and cyclooctylsulfonyl areexemplified. Preferably C3-C6 cycloalkylsulfonyl is exemplified.

In the present specification, a term of “cycloalkylsulfonyloxy” includesa group in which an oxygen atom is substituted with one“cycloalkylsulfonyl” above. For example, cyclopropylsulfonyloxy,cyclobutylsulfonyloxy, cyclopentylsulfonyloxy, cyclohexylsulfonyloxy,cycloheptylsulfonyloxy, and cyclooctylsulfonyloxy are exemplified.Preferably C3-C6 cycloalkylsulfonyloxy is exemplified.

In the present specification, a term of “cycloalkenylthio” includes agroup in which a sulfur atom is substituted with one “cycloalkenyl”above. For example, cyclopropenylthio, cyclobutenylthio,cyclopentenylthio, cyclohexenylthio, cycloheptenylthio, andcyclooctenylthio are exemplified. Preferably C3-C6 cycloalkenylthio isexemplified. When a number of carbon is specified, it means“cycloalkenylthio” having the carbon number within the range.

In the present specification, a term of “cycloalkenylsulfinyl” includesa group in which sulfinyl is substituted with one “cycloalkenyl” above.For example, cyclopropenylsulfinyl, cyclobutenylsulfinyl,cyclopentenylsulfinyl, cyclohexenylsulfinyl, cycloheptenylsulfinyl, andcyclooctenylsulfinyl are exemplified. Preferably C3-C6cycloalkenylsulfinyl is exemplified.

In the present specification, a term of “cycloalkenylsulfonyl” includesa group in which sulfonyl is substituted with one “cycloalkenyl” above.For example, cyclopropenylsulfonyl, cyclobutenylsulfonyl,cyclopentenylsulfonyl, cyclohexenylsulfonyl, cycloheptenylsulfonyl, andcyclooctenylsulfonyl are exemplified. Preferably C3-C6cycloalkenylsulfonyl is exemplified.

In the present specification, a term of “cycloalkenylsulfonyloxy”includes a group in which an oxygen atom is substituted with one“cycloalkenylsulfonyl” described above. For example,cyclopropenylsulfonyloxy, cyclobutenylsulfonyloxy,cyclopentenylsulfonyloxy, cyclohexenylsulfonyloxy,cycloheptenylsulfonyloxy, and cyclooctenylsulfonyloxy are exemplified.Preferably C3-C6 cycloalkenylsulfonyloxy is exemplified.

In the present specification, a term of “alkyloxycarbonyl” includes agroup in which carbonyl is substituted with one “alkyloxy” above. Forexample, methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl,isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl andn-pentyloxycarbonyl are exemplified. Preferably C1-C4 alkyloxycarbonylis exemplified. Moreover, C1-C2 alkyloxycarbonyl is further preferable.

In the present specification, a term of “alkenyloxycarbonyl” includes agroup in which carbonyl is substituted with one “alkenyloxy” above. Forexample, vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl,2-butenyloxycarbonyl and 2-pentenyloxyarbonyl are exemplified.Preferably C2-C4 alkyloxycarbonyl is exemplified.

In the present specification, a term of “alkynyloxycarbonyl” includes agroup in which carbonyl is substituted with one “alkynyloxy” above. Forexample, ethynyloxycarbonyl, 1-propynyloxycarbonyl,2-propynyloxycarbonyl, 2-butynyloxyarbonyl and 2-pentynyloxycarbonyl areexemplified. Preferably C2-C4 alkynyloxycarbonyl is exemplified.

In the present specification, a term of “acyl” includes alkylcarbonylwherein the part of alkyl is “alkyl” before, alkenylcarbonyl wherein thepart of alkenyl is “alkenyl” before, alkynylcarbonyl wherein the part ofalkynyl is “alkynyl” before, cycloalkylcarbonyl wherein the part ofcycloalkyl is “cycloalkyl” before, arylcarbonyl wherein the part of arylis “aryl” below, heteroarylcarbonyl wherein the part of heteroaryl is“heteroaryl” below and non-aromatic heterocycliccarbonyl wherein thepart of non-aromatic heterocyclic group is “non-aromatic heterocyclicgroup” below. “Alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl”, “aryl”,“heteroaryl” and “non-aromatic heterocyclic group” may be substitutedrespectively with substituent groups exemplified in “optionallysubstituted alkyl”, “optionally substituted alkenyl”, “optionallysubstituted alkynyl”, “optionally substituted cycloalkyl”, “optionallysubstituted aryl”, “optionally substituted heteroaryl” and “optionallysubstituted non-aromatic heterocyclic group” below. Examples of the acylgroup include acetyl, propionyl, butyroyl, cyclohexylcarbonyl, benzoyl,pyridinecarbonyl and the like.

In the present specification, a term of “optionally substituted amino”includes an amino group which may be substituted with one or twogroup(s) of “alkyl” before, “alkenyl” before, “alkynyl” before,“cycloalkyl” before, “cycloalkynyl” before, “aryl” below, “heteroaryl”below, “acyl” before, “alkyloxycarbonyl” before, “alkenyloxycarbonyl”before, “alkynyloxycarbonyl” before, “alkyl sulfonyl”,“alkenylsulfonyl”, “alkynylsulfonyl”, “arylsulfonyl” and/or“heteroarylsulfonyl” before. Examples of the optionally substitutedamino group include amino, methylamino, dimethylamino, ethylamino,diethylamino, ethylmethylamino, benzylamino, acetylamino, benzoylamino,methyloxycarbonylamino and methanesulfonylamino. Preferably, amino,methylamino, dimethylamino, ethylmethylamino, diethylamino, acetylaminoand methanesulfonylamino are exemplified.

In the present specification, a term of “optionally substitutedcarbamoyl” includes an aminocarbonyl group wherein the part ofoptionally substituted amino is “optionally substituted amino” beforeand examples of the optionally substituted carbamoyl group includescarbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl,N-benzylcarbamoyl, N-acetylcarbamoyl and N-methylsulfonylcarbamoyl etc.Preferably, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl andN-methylsulfonylcarbamoyl etc. are exemplified.

In the present specification, a term of “optionally substitutedsulfamoyl” includes an aminosulfonyl group wherein the part ofoptionally substituted amino is “optionally substituted amino” beforeand examples of the optionally substituted sulfamoyl group includesulfamoyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-ethyl-N-methylsulfamoyl, N,N-diethylsulfamoyl, N-phenylsulfamoyl, N-benzylsulfamoyl,N-acetylsulfamoyl and N-methyl sulfonylsulfamoyl etc. Preferably,sulfamoyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl andN-methylsulfonylsulfamoyl etc. are exemplified.

In the present specification, a term of “alkylene” means a straight orbranched alkylene group having one to eight carbon atom(s) and forexample, methylene, ethylene, 1-methylethylene, trimethylene,1-methyltrimethylene, pentamethylene, hexamethylene, and the like.Preferably C1-C4 alkylene is exemplified. Moreover, C1-C2 alkylene isfurther preferred.

In the present specification, a term of “aryl” includes an aromaticmonocyclic or aromatic fused cyclic hydrocarbons and it may be fusedwith “cycloalkyl” before, “cycloalkenyl” before or “non-aromaticheterocyclic group” below at any possible position. Both of monocyclicring and fused ring may be substituted at any position and for example,phenyl, 1-naphthyl, 2-naphthyl, anthryl, tetrahydronaphthyl,1,3-benzodioxolyl, 1,4-benzodioxanyl etc. are exemplified. Phenyl,1-naphthyl and 2-naphthyl are preferred. Moreover, phenyl is furtherpreferred.

In the present specification, a term of “non-aromatic heterocyclicgroup” of R¹, R², R³, R⁴, R⁵, R⁶, R^(1a), R^(2a), R^(3a), R^(4a),R^(5a), R^(6a), R^(11a), R^(12a), R^(13a) and R^(14a) includes a 5- to7-membered non-aromatic heterocyclic ring containing one or more ofheteroatom(s) selected independently from oxygen, sulfur and nitrogenatoms or a multicyclic ring formed by fusing the two or more ringsthereof. For example, pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl), pyrrolinyl (e.g., 3-pyrrolinyl), imidazolidinyl (e.g.,2-imidazolidinyl), imidazolinyl (e.g., imidazolinyl), pyrazolidinyl(e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g.,pyrazolinyl), piperidyl (e.g., piperidino, 2-piperidyl), piperazinyl(e.g., 1-piperazinyl), indolinyl (e.g., 1-indolinyl), isoindolinyl(e.g., isoindolinyl), morpholinyl (e.g., morpholino, 3-morpholinyl) etc.are exemplified.

In the present specification, a term of “non-aromatic heterocyclicgroup” of R⁸, R⁹, R¹¹, R¹², R¹⁴, R^(18a) and R^(9a) includes a 5- to7-membered non-aromatic heterocyclic ring containing one or more ofheteroatom(s) selected independently from oxygen, sulfur and nitrogenatoms or a multicyclic ring formed by fusing the two or more ringsthereof. For example, pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl), piperidyl (e.g., piperidino, 2-piperidyl), piperazinyl(e.g., 1-piperazinyl), morpholinyl (e.g., morpholino, 3-morpholinyl)etc. are exemplified.

In the present specification, a term of “heteroaryl” in R¹, R², R³, R⁴,R⁵, R⁶, R^(1a), R^(2a), R^(3a), R^(4a), R^(5a), R^(6a), R^(11a),R^(12a), R^(13a) and R^(14a) includes a 5- to 6-membered aromatic ringcontaining one or more of heteroatom(s) selected independently fromoxygen, sulfur and nitrogen atoms and it may be fused with “cycloalkyl”before, “aryl” before, “non-aromatic heterocyclic group” before or otherheteroaryl at any possible position. The heteroaryl group may besubstituted at any position whenever it is a monocyclic ring or a fusedring. For example, pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl),furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl),imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g.,1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl),isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl(e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl,4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl (e.g.,1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl(e.g., 1,3,4-thiadiazolyl), indolidinyl (e.g., 2-indolidinyl,6-indolidinyl), isoindolynyl (e.g., 2-isoindolynyl), indolyl (e.g.,1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl), purinyl(e.g., 8-purinyl), quinolidinyl (e.g., 2-quinolidinyl), isoquinolyl(e.g., 3-isoquinolyl), quinolyl (e.g., 2-quinolyl, 5-quinolyl),phtharazinyl (e.g., 1-phtharazinyl), naphthylidinyl (e.g.,2-naphthylidinyl), quinolanyl (e.g., 2-quinolanyl), quinazolinyl (e.g.,2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g.,2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 4-carbazolyl),phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl(e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g.,1-dibenzofuranyl, 2-dibenzofuranyl), benzoimidazolyl (e.g.,2-benzoimidazolyl), benzoisoxazolyl (e.g., 3-benzoisoxazolyl),benzooxazolyl (e.g., 2-benzooxazolyl), benzooxadiazolyl (e.g.,4-benzooxadiazolyl), benzoisothiazolyl (e.g., 3-benzoisothiazolyl),benzothiazolyl (e.g., 2-benzothiazolyl), benzofuryl (e.g.,3-benzofuryl), benzothienyl (e.g., 2-benzothienyl), dibenzothienyl(e.g., 2-dibenzothienyl) and benzodioxolyl (e.g., 1,3-benzodioxolyl)etc. are exemplified.

In the present specification, a term of “heteroaryl” in R⁸, R⁹, R¹¹,R¹², R¹⁴, R^(8a) and R^(9a) includes a 5- to 6-membered aromatic ringcontaining one or more of heteroatom(s) selected independently fromoxygen, sulfur and nitrogen atoms and it may be fused with “cycloalkyl”before, “aryl” before, “non-aromatic heterocyclic group” before or otherheteroaryl at any possible position. The heteroaryl group may besubstituted at any position whenever it is a monocyclic ring or a fusedring. For example, furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g.,2-thienyl, 3-thienyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl),pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g.,3-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g.,2-oxazolyl), thiazolyl (e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl,3-pyridyl, 4-pyridyl), pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl),oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl (e.g.,1,3,4-thiadiazolyl), benzoimidazolyl (e.g., 2-benzoimidazolyl),benzoisoxazolyl (e.g., 3-benzoisoxazolyl), benzooxazolyl (e.g.,2-benzooxazolyl), benzofuryl (e.g., 3-benzofuryl), benzothienyl (e.g.,2-benzothienyl) etc. are exemplified.

In the present specification, a term of “aryloxy” includes a group inwhich an oxygen atom is substituted with one “aryl” before and forexample, phenyloxy and naphthyloxy etc. are exemplified.

In the present specification, a term of “arylthio” includes a group inwhich a sulfur atom is substituted with one “aryl” before and forexample, phenylthio and naphthylthio etc. are exemplified.

In the present specification, a term of “arylsulfinyl” includes a groupin which sulfinyl is substituted with one “aryl” before and for example,phenylsulfinyl and naphthylsulfinyl etc. are exemplified.

In the present specification, a term of “arylsulfonyl” includes a groupin which sulfonyl is substituted with one “aryl” before and for example,phenylsulfonyl and naphthylsulfoinyl etc. are exemplified.

In the present specification, examples of “arylsulfonyloxy includephenylsulfonyloxy and naphthylsulfonyloxy etc.

In the present specification, a term of “aryloxycarbonyl” includes agroup in which carbonyl is substituted with one “aryloxy” before and forexample, phenyloxycarbonyl, 1-naphthyloxycarbonyl and2-naphthyloxycarbonyl etc. are exemplified.

In the present specification, a term of “heteroaryloxy” includes a groupin which an oxygen atom is substituted with one “heteroaryl” before. Forexample, pyrrolyloxy, furyloxy, thienyloxy, imidazolyloxy, pyrazolyloxy,isothiazolyloxy, isoxazolyloxy, oxazolyloxy, thiazolyloxy, pyridyloxy,pyrazinyloxy, pyrimidinyloxy, pyridazinyloxy, tetrazolyloxy,oxadiazolyloxy, thiadiazolyloxy, indolidinyloxy, isoindolynyloxy,indolyloxy, indazolyloxy, purinyloxy, quinolidinyloxy, isoquinolyloxy,quinolyloxy, phtharazinyloxy, naphthylidinyloxy, quinolanyloxy,quinazolinyloxy, cinnolinyloxy, pteridinyloxy, carbazolyloxy,phenanthridinyloxy, acridinyloxy, dibenzofuranyloxy, benzoimidazolyloxy,benzoisoxazolyloxy, benzooxazolyloxy, benzooxadiazolyloxy,benzoisothiazolyloxy, benzothiazolyloxy, benzofuryloxy, benzothienyloxy,dibenzothienyloxy and benzodioxolyloxy are exemplified. Preferablyfuryloxy, thienyloxy, imidazolyloxy, pyrazolyloxy, isothiazolyloxy,isoxazolyloxy, oxazolyloxy, thiazolyloxy, pyridyloxy, pyrazinyloxy,pyrimidinyloxy and pyridazinyloxy are exemplified.

In the present specification, a term of “heteroarylthio” includes agroup in which a sulfur atom is substituted with one “heteroaryl”before. For example, pyrrolylthio, furylthio, thienylthio,imidazolylthio, pyrazolylthio, isothiazolylthio, isoxazolylthio,oxazolylthio, thiazolylthio, pyridylthio, pyrazinylthio,pyrimidinylthio, pyridazinylthio, tetrazolylthio, oxadiazolylthio,thiadiazolylthio, indolidinylthio, isoindolynylthio, indolylthio,indazolylthio, purinylthio, quinolidinylthio, isoquinolylthio,quinolylthio, phtharazinylthio, naphthylidinylthio, quinolanylthio,quinazolinylthio, cinnolinylthio, pteridinylthio, carbazolylthio,phenanthridinylthio, acridinylthio, dibenzofuranylthio,benzoimidazolylthio, benzoisoxazolylthio, benzooxazolylthio,benzooxadiazolylthio, benzoisothiazolylthio, benzothiazolylthio,benzofurylthio, benzothienylthio, dibenzothienylthio andbenzodioxolylthio etc. are exemplified. Preferably furylthio,thienylthio, imidazolylthio, pyrazolylthio, isothiazolylthio,isoxazolylthio, oxazolylthio, thiazolylthio, pyridylthio, pyrazinylthio,pyrimidinylthio, and pyridazinylthio etc. are exemplified.

In the present specification, a term of “heteroarylsulfinyl” includes agroup in which sulfinyl is substituted with one “heteroaryl” before. Forexample, pyrrolylsulfinyl, furylsulfinyl, thienylsulfinyl,imidazolylsulfinyl, pyrazolylsulfinyl, isothiazolylsulfinyl,isoxazolylsulfinyl, oxazolylsulfinyl, thiazolylsulfinyl,pyridylsulfinyl, pyrazinylsulfinyl, pyrimidinylsulfinyl,pyridazinylsulfinyl, tetrazolylsulfinyl, oxadiazolylsulfinyl,thiadiazolylsulfinyl, indolidinylsulfinyl, isoindolylsulfinyl,indolylsulfinyl, indazolylsulfinyl, purinylsulfinyl,quinolidinylsulfinyl, isoquinolylsulfinyl, quinolylsulfinyl,phtharazinylsulfinyl, naphthylidinylsulfinyl, quinolanylsulfinyl,quinazolinylsulfinyl, cinnolinylsulfinyl, pteridinylsulfinyl,carbazolylsulfinyl, phenanthridinylsulfinyl, acridinylsulfinyl,dibenzofuranylsulfinyl, benzoimidazolylsulfinyl,benzoisoxazolylsulfinyl, benzooxazolylsulfinyl,benzooxadiazolylsulfinyl, benzoisothiazolylsulfinyl,benzothiazolylsulfinyl, benzofurylsulfinyl, benzothienylsulfinyl,dibenzothienylsulfinyl and benzodioxolylsulfinyl etc. are exemplified.Preferably furylsulfinyl, thienylsulfinyl, imidazolyl sulfinyl,pyrazolylsulfinyl, isothiazolylsulfinyl, isoxazolylsulfinyl,oxazolylsulfinyl, thiazolylsulfinyl, pyridylsulfinyl, pyrazinylsulfinyl,pyrimidinylsulfinyl and pyridazinylsulfinyl etc. are exemplified.

In the present specification, a term of “heteroarylsulfonyl” includes agroup in which sulfonyl is substituted with one “heteroaryl” before. Forexample, pyrrolylsulfonyl, furylsulfonyl, thienylsulfonyl,imidazolylsulfonyl, pyrazolylsulfonyl, isothiazolylsulfonyl,soxazolylsulfonyl, oxazolylsulfonyl, thiazolylsulfonyl, pyridylsulfonyl,pyrazinylsulfonyl, pyrimidinylsulfonyl, pyridazinylsulfonyl,tetrazolylsulfonyl, oxadiazolylsulfonyl, thiadiazolylsulfonyl,indolizinylsulfonyl, isoindolylsulfonyl, indolylsulfonyl,indazolylsulfonyl, purinylsulfonyl, quinolidinylsulfonyl,isoquinolylsulfonyl, quinolylsulfonyl, phtharazinylsulfonyl,naphthilidinylsulfonyl, quinolanylsulfonyl, quinazolinylsulfonyl,cinnolinylsulfonyl, pteridinylsulfonyl, carbazolylsulfonyl,phenanthridinylsulfonyl, acridinylsulfonyl, dibenzofuranylsulfonyl,benzoimidazolylsulfonyl, benzoisoxazolylsulfonyl, benzooxazolylsulfonyl,benzooxadiazolylsulfonyl, benzoisothiazolylsulfonyl,benzothiazolylsulfonyl, benzofurylsulfonyl, benzothienylsulfonyl,dibenzothienylsulfonyl and benzodioxolylsulfonyl are exemplified.Preferably furylsulfonyl, thienylsulfonyl, imidazolylsulfonyl,pyrazolylsulfonyl, isothiazolylsulfonyl, isoxazolylsulfonyl,oxazolylsulfonyl, thiazolylsulfonyl, pyridylsulfonyl, pyrazinylsulfonyl,pyrimidinylsulfonyl and pyridazinylsulfonyl are exemplified.

In the present specification, a term of “heteroarylsulfonyloxy” includesa group in which an oxygen atom is substituted with one“heteroarylsulfonyl” before. For example, pyrrolylsulfonyloxy,furylsulfonyloxy, thienylsulfonyloxy, imidazolyl sulfonyloxy,pyrazolylsulfonyloxy, isothiazolylsulfonyloxy, isoxazolylsulfonyloxy,oxazolylsulfonyloxy, thiazolylsulfonyloxy, pyridylsulfonyloxy,pyrazinylsulfonyloxy, pyrimidinylsulfonyloxy, pyridazinylsulfonyloxy,tetrazolylsulfonyloxy, oxadiazolylsulfonyloxy, thiadiazolylsulfonyloxy,indolizinylsulfonyloxy, isoindolylsulfonyloxy, indolylsulfonyloxy,indazolylsulfonyloxy, purinylsulfonyloxy, quinolidinylsulfonyloxy,isoquinolylsulfonyloxy, quinolylsulfonyloxy, phtharazinylsulfonyloxy,naphthilidinylsulfonyloxy, quinolanyl sulfonyloxy,quinazolinylsulfonyloxy, cinnolinylsulfonyloxy, pteridinyl sulfonyloxy,carbazolylsulfonyloxy, phenanthridinylsulfonyloxy, acridinylsulfonyloxy,dibenzofuranylsulfonyloxy, benzoimidazolylsulfonyloxy,benzoisoxazolylsulfonyloxy, benzooxazolylsulfonyloxy,benzooxadiazolylsulfonyloxy, benzoisothiazolylsulfonyloxy,benzothiazolylsulfonyloxy, benzofurylsulfonyloxy,benzothienylsulfonyloxy, dibenzothienylsulfonyloxy andbenzodioxolylsulfonyloxy etc. are exemplified. Preferably,furylsulfonyloxy, thienylsulfonyloxy, imidazolylsulfonyloxy,pyrazolylsulfonyloxy, isothiazolylsulfonyloxy, isoxazolylsulfonyloxy,oxazolylsulfonyloxy, thiazolylsulfonyloxy, pyridylsulfonyloxy,pyrazinylsulfonyloxy, pyrimidinylsulfonyloxy and pyridazinylsulfonyloxyetc. are exemplified.

In the present specification, a term of “aromatic carbocyclic ring”includes an aromatic monocyclic or aromatic fused carbocyclic ring andfor example, a benzene ring, a naphthalene ring and an anthracene ringare exemplified. A benzene ring is preferred.

In the present specification, a term of “aromatic heterocyclic ring”includes an aromatic monocyclic or aromatic fused heterocyclic ring. Forexample, a pyrrole ring, a furan ring, a thiophen ring, a pyrazole ring,an imidazole ring, an isothiazole ring, an isoxazole ring, an oxazolering, a thiazole ring, a pyrazine ring, a pyrimidine ring, a pyridazinering, a tetrazole ring, an oxadiazole ring, a thiadiazole ring, anindolizine ring, an isoindole ring, an indole ring, an indazole ring, apurine ring, a quinolidine ring, an isoquinoline ring, a quinoline ring,a phtharazine ring, a naphthyridine ring, a quinolane ring, aquinazoline ring, a cinnoline ring, a pteridine ring, a carbazole ring,a phenanthridine ring, an acridine ring, a dibenzofuran ring, abenzoimidazole ring, a benzoisoxazole ring, a benzooxazole ring, abenzooxadiazole ring, a benzoisothiazole ring, a benzothiazole ring, abenzofuran ring, a benzothiophen ring, a dibenzothiophen ring and abenzodixolane ring are exemplified. Preferably a pyridine ring, a furanring and a thiophen ring are exemplified.

In the present specification, a term of “C1-C6 alkylene” includes astraight or branched alkylene group having one to six carbon atom(s),and for example, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH(CH₃)CH₂—,—C(CH₃)₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂— and—CH₂CH₂CH₂CH₂CH₂CH₂— are exemplified. Preferably, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂— are exemplified.

In the present specification, a term of “alkylene optionally containingone or two heteroatom(s)” of “optionally substituted alkylene optionallycontaining one or two heteroatom(s)” includes a straight or branchedalkylene group having one to six carbon atoms, optionally containing oneor two heteroatom(s) which may be substituted with “alkyl” above, andfor example, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, —CH₂O—, —OCH₂—, —CH₂CH₂O—,—OCH₂CH₂—, —CH₂S—, —SCH₂—, —CH₂CH₂S—, —SCH₂CH₂—, —CH₂CH₂OCH₂CH₂—,—OCH₂CH₂O—, —OCH₂O—, —NHCH₂—, —N(CH₃)CH₂—, —N⁺(CH₃)₂CH₂—, —NHCH₂CH₂CH₂—and —N(CH₃)CH₂CH₂CH₂— etc. are exemplified. Preferably, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —OCH₂CH₂O—, —OCH₂O— and —N(CH₃)CH₂CH₂CH₂—are exemplified.

In the present specification, a term of “alkenylene optionallycontaining one or two heteroatom(s)” of “optionally substituted alkyleneoptionally containing one or two heteroatom(s)” includes a straight orbranched alkenylene group having two to six carbon atoms, optionallycontaining one or two heteroatom(s) which may be substituted with“alkyl” above, and for example, —CH═CHCH═CH—, —CH═CHO—, —OCH═CH—,—CH═CHS—, —SCH═CH—, —CH═CHNH—, —NHCH═CH—, —CH═CH—CH═N— and —N═CH—CH═CH—are exemplified. Preferably, —CH═CHCH═CH—, —CH═CHCH═N— and —N═CHCH═CH—are exemplified.

In the present specification, a term of “alkynylene optionallycontaining one or two heteroatom(s)” includes a straight or branchedalkynylene group having two to six carbon atoms, optionally containingone or two heteroatom(s) which may be substituted with “alkyl” above,and for example, —C≡CCH₂—, —CH₂C≡CCH₂—, —CH₂C≡CCH₂O—, —OCH₂C≡CH—,—CH₂C≡CCH₂S—, —SCH₂C≡CH—, —CH₂C≡CCH₂NH—, —NHCH₂C≡CH—, —CH₂C≡CCH₂N(CH₃)—and —N(CH₃)CH₂C≡CH— are exemplified. Especially, —CH₂C≡CCH₂— and—OCH₂C≡CH— are preferred.

In the present specification, a term of “3- to 8-memberednitrogen-containing non-aromatic heterocyclic ring” includes a ring ofthe formula of

In the present specification, a term of “3- to 8-nitrogen-containingaromatic heterocyclic ring” includes a 3- to 8-membered aromaticheterocyclic ring containing one or more of nitrogen atom(s), andfurther optionally an oxygen atom and/or sulfur atom in the ring. Forexample, pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl(e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl,3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl), isoxazolyl (e.g.,3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl (e.g.,2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl(e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl),pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl (e.g., 1H-tetrazolyl),oxadiazolyl (e.g., 1,3,4-oxadiazolyl) and thiadiazolyl (e.g.,1,3,4-thiadiazolyl) are exemplified.

In the present specification, a term of “4- to 8-memberednitrogen-containing heterocyclic ring containing one or two nitrogenatom(s)” means a ring of the formula of

In the present specification, examples of substituents in “optionallysubstituted alkyl”, “optionally substituted alkyloxy”, “optionallysubstituted alkylthio”, “optionally substituted alkylsulfinyl”,“optionally substituted alkylsulfonyl”, “optionally substitutedalkylsulfonyloxy” and “the optionally substituted alkyloxycarbonyl”include cycloalkyl, alkylene optionally containing one or twoheteroatom(s), hydroxy, oxo, alkyloxy optionally substituted with asubstituent group A at one to three position(s), mercapto, alkylthio, ahalogen atom, nitro, cyano, carboxy, alkyloxycarbonyl, optionallysubstituted amino, optionally substituted carbamoyl, acyl, aryloptionally substituted with a substituent group B at one to threeposition(s) (e.g., phenyl), heteroaryl optionally substituted with asubstituent group C at one to three position(s) (e.g., pyridyl, furyl,thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl), an optionallysubstituted non-aromatic heterocyclic ring group which may besubstituted with a substituent group C at one to three position(s)(e.g., morpholinyl, pyrrolidinyl, piperazinyl), aryloxy optionallysubstituted with a substituent group B at one to three position(s)(e.g., phenyloxy), alkylsulfonyl and the like. These can be substitutedwith one to three substituent(s) at any possible position.

In the present specification, examples of substituents in “optionallysubstituted alkenyl”, “optionally substituted alkynyl”, “optionallysubstituted alkenyloxy”, “optionally substituted alkynyloxy”,“optionally substituted alkenylthio”, “optionally substitutedalkynylthio”, “optionally substituted alkenyloxycarbonyl”, “optionallysubstituted alkynyloxycarbonyl”, “optionally substituted cycloalkyl”,“optionally substituted cycloalkenyl”, “optionally substitutedcycloalkyloxy, “optionally substituted cycloalkenyloxy”, “optionallysubstituted cycloalkylthio”, “optionally substituted cycloalkenylthio”,“optionally substituted cyclo alkyl sulfinyl”, “optionally substitutedcycloalkenylsulfinyl”, “optionally substituted cycloalkylsulfonyl”,“optionally substituted cycloalkenylsulfonyl”, “optionally substitutedcycloalkylsulfonyloxy”, “optionally substitutedcycloalkenylsulfonyloxy”, “optionally substituted alkenyloxycarbonyl”,“optionally substituted C1-C6 alkylene”, “optionally substitutedalkylene”, “optionally substituted alkenylene” and “the optionallysubstituted alkynylene” include alkyl optionally substituted with asubstituent group D at one to three position(s), cycloalkyl, alkyleneoptionally containing one or two heteroatom(s), hydroxy, oxo, alkyoxyloptionally substituted with a substituent group A at one to threeposition(s), mercapto, alkylthio, halogen atom, nitro, cyano, carboxy,alkyloxycarbonyl, optionally substituted amino, optionally substitutedcarbamoyl, acyl acyloxy, aryl optionally substituted with a substituentgroup B at one to three position(s) (e.g., phenyl), heteroaryloptionally substituted with a substituent group C at one to threeposition(s) (e.g., pyridyl, furyl, thienyl, imidazolyl, oxazolyl,thiazolyl, pyrazolyl), non-aromatic heterocyclic group optionallysubstituted with a substituent group C at one to three position(s)(e.g., morpholinyl, pyrrolidinyl, piperazinyl), aryloxy optionallysubstituted with a substituent group C at one to three position(s)(e.g., phenyloxy), alkylsulfonyl and the like. These can be substitutedwith one or more substituent(s) at any possible position.

In the present specification, examples of substituents in “optionallysubstituted aryl”, “optionally substituted phenoxy”, “optionallysubstituted aryloxy”, “optionally substituted phenylthio”, “optionallysubstituted arylthio”, “optionally substituted arylsulfinyl”,“optionally substituted arylsulfonyl”, “optionally substitutedarylsulfonyloxy”, “optionally substituted heteroaryl”, “optionallysubstituted heteroaryloxy”, “optionally substituted heteroarylthio”,“optionally substituted heteroarylsulfinyl”, “optionally substitutedheteroarylsulfonyl”, “optionally substituted heteroarylsulfonyloxy” and“optionally substituted non-aromatic heterocyclic group” include alkyloptionally substituted with a substituent group D at one to threeposition(s), cycloalkyl, alkenyl, alkynyl, hydroxy, alkyloxy optionallysubstituted with a substituent group A at one to three position(s),aryloxy optionally substituted with a substituent group B at one tothree position(s) (e.g., phenoxy), mercapto, alkylthio, a halogen atom,nitro, cyano, carboxy, alkyloxycarbonyl, acyl, alkylsulfonyl, optionallysubstituted amino, optionally substituted carbamoyl, aryl optionallysubstituted with a substituent group B at one to three position(s)(e.g., phenyl), heteroaryl optionally substituted with a substituentgroup C at one to three position(s) (e.g., pyridyl, furyl, thienyl,imidazolyl, oxazolyl, thiazolyl, pyrazolyl), non-aromatic heterocyclicgroup optionally substituted with a substituent group C at one to threeposition(s) (e.g., morpholinyl, pyrrolidinyl, piperazinyl) and the like.These can be substituted with one or more substituent(s) at any possibleposition.

Substituent group A is comprised of a halogen atom and phenyl optionallysubstituted with one to three substituent(s) selected from theSubstituent group B.

Substituent group B is comprised of a halogen atom, alkyl, alkyloxy,cyano and nitro.

Substituent group C is comprised of a halogen atom and alkyl.

Substituent group D is comprised of a halogen atom and alkyloxy.

In the specification a term of “carboxy equivalent” means a biologicalequivalent and includes substituents having the same polar effect as acarboxy group. For example, —CONHCN, —CONHOH, —CONHOMe, —CONHOt-Bu,—CONHOCH₂Ph, —SO₃H, —SO₂NH₂, —SO₂NHMe, —NHCONH₂, —NHCONMe₂, —P(═O)(OH)₂,—P(═O)(OH)(OEt), —P(═O)(OH)NH₂, —P(═O)(OH)NHMe, —CONHSO₂Ph, —SO₂NHCOMe,—SO₂NHCOPh, and the formulae of;

are exemplified. Preferably, —CONHOt-Bu, —CONHOCH₂Ph, —SO₃H, —CONHSO₂Ph,—SO₂NHCOMe, —SO₂NHCOPh, and the formulae of;

are exemplified.

A compound of the general formula (I) includes a compound of the generalformula of

Among the compounds of the general formulae above, the compounds of theformulae of

are preferable, and moreover the compounds of the formulae of

are further preferable.

Examples of the group of the formula:

include the group of the formula of

Among the groups above, the groups of the formula of

is preferable.

Groups of preferred substituents in the ring A, ring B, —X¹═X²—X³═X⁴—,X⁵, R¹˜R⁴, R⁶˜R⁹, M, Y, L¹, L², L³, n and q of the compound of generalformula (I) are shown with (Ia) to (III). Compounds having possiblecombination of them are preferable.

In the ring A, (Ia) a benzen ring, a furan ring, a thiophen ring or apyridine ring is preferable, and further (Ib) a benzene ring or apyridine ring is more preferable.

In the ring B, (Ic) a group of the formula of

is preferable, (Id) a group of the formula of

is more preferable, and (Ie) a group of the formula of

is most preferable.

In —X¹═X²—X³═X⁴—, (If) the formula of —C(R¹)═C(R²)—N═C(R⁴)—,—C(R¹)═C(R²)—C(R³)═N— or —C(R¹)═C(R²)—C(R³)═C(R⁴)— is preferable, andfurther (Ig) the formula of —C(R¹)═C(R²)—C(R³)═C(R⁴)— is morepreferable.

In X⁵, (Ih) —N═, —CH═, —C(a halogen atom)= or —C(alkyl)= is preferable,and further (Ii) —N═ or —CH═ is more preferable.

In R⁶, (Ij) a hydrogen atom, optionally substituted alkyl or —Z—R¹⁰ ispreferable, and further (Ik) —Z—R¹⁰ is more preferable.

In R¹ to R⁴ a preferable group is independent, and (Il) a hydrogen atom,a halogen atom, optionally substituted alkyl, optionally substitutedalkoxy, optionally substituted amino, cyano, nitro, optionallysubstituted aryl, optionally substituted heteroaryl or —Z—R¹⁰ ispreferable and further (Im) a hydrogen atom, a halogen atom, optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedaryl or optionally substituted heteroaryl is more preferable, providedthat at least one of to R⁶ is —Z—R¹⁰.

In R⁷, (In) optionally substituted C1-C6 alkyloxy, optionallysubstituted C1-C6 alkylthio, optionally substituted C5-C6 cycloalkyloxyor optionally substituted aryloxy is preferable, and further (Io)optionally substituted C1-C6 alkyloxy or optionally substituted C1-C6alkylthio is more preferable.

In R⁸, (Ip) a halogen atom, optionally substituted alkyl, cyano, nitro,optionally substituted aryl or optionally substituted heteroaryl ispreferable, and further (Iq) a halogen atom or optionally substitutedalkyl is further preferable.

In R⁹, (Ir) optionally substituted alkyl or oxo is preferable andfurther (Is) alkyl is preferable.

In R¹⁰, (It) carboxy, alkyloxycarbonyl, optionally substituted carbamoylor a carboxy equivalent is preferable, and further (Iu) carboxy is morepreferable.

In M, (Iv) sulfonyl or carbonyl is preferable and further (Iw) sulfonylis more preferable.

In Y, (Ix) a single bond or optionally substituted alkylene optionallycontaining ore or two heteroatom(s) is preferable, and further (Iy) asingle bond is more preferable.

In L¹, (Iz) a single bond, optionally substituted alkylene optionallycontaining ore or two heteroatom(s) or —NH— is preferable, and further(IIa) a single bond is more preferable.

In L², (IIb) a single bond, optionally substituted alkylene optionallycontaining ore or two heteroatom(s) or —NH— is preferable, and further(IIc) a single bond is more preferable.

In L³, (IId) a single bond, methylene or —O-methylene is preferable, andmoreover (IIe) a single bond or methylene is more preferable. Further,(IIf) a single bond or (IIg) methylene is most preferable.

In n, (IIh) 0, 1 or 2 is preferable, and further (IIi) 0 is morepreferable.

In q, (IIj) 0 or 1 is preferable, and further (IIk) 1 or (III) 0 is morepreferable.

Groups of preferred substituents in the ring C, X⁵, R¹ to R⁴, R⁹ to R¹⁰,R¹³ to R¹⁴, M, L³, n and q of the compound of general formula (II) areshown with (Id) above to (Ii) above, (Il) above to (Iw) above, (IIh)above to (IIl) above and (IIm) to (IIo). Compounds having possiblecombination of them are preferable.

In the ring C, (Id) above is preferable and further (Ie) above is morepreferable.

In X⁵, (Ih) above is preferable and further (Ii) above is morepreferable.

In R¹ to R⁴ a preferable group is independent, (Il) above is preferableand further (Im) above is more preferable.

In R⁹, (Ir) above is preferable and further (Is) above is morepreferable.

In R¹⁰, (It) above is preferable and further (Iu) above is morepreferable.

In R¹³, (In) above is preferable and further (Io) above is morepreferable.

In R¹⁴, (Ip) above is preferable and further (Iq) above is morepreferable.

In M, (Iv) above is preferable and further (Iw) above is morepreferable.

In n, (IIh) above is preferable and further (IIi) above is morepreferable.

In q, (IIj) above is preferable and further (IIk) above or (IIl) aboveis more preferable.

In Z, (IIm) CH, C(R¹⁴) or N is preferable, and further (IIn) CH or (IIo)N is more preferable.

Groups of preferred substituents in the ring A^(a), the ring B^(a),—X^(1a)═X^(2a)—X^(3a)═X^(4a)—, R^(1a) to R^(10a), Y^(a), Z^(a), ma, naand pa of the compound of general formula (I-a) are shown with (Ia)above to (Id) above, (Il) above to (Im) above, (Ip) above to (Iq) above,(Is) above, (Iu) above, (Iy) above, (IIh) above to (IIk) above and (IIp)to (IIIc). Compounds having possible combination of them are preferable.

In the ring A^(a), (Ia) above is preferable and further (Ib) above ismore preferable.

In the ring B^(a), (Ic) above is preferable and further (Id) above ismore preferable.

In the formula of —X^(1a)═X^(2a)—X^(3a)═X^(4a)—, (IIp) a formula of—C(R^(1a))═C(R^(2a))—N═C(R^(4a))—, —C(R^(1a))═C(R^(2a))—C(R^(3a))═N— or—C(R^(1a))═C(R^(2a))—C(R^(3a))═C(R^(4a))— is preferable, and further(IIq) a formula of —C(R^(1a))═C(R^(2a))—C(R^(3a))═C(R^(4a))— is morepreferable.

In R^(1a) and R^(6a) a preferable group is independent, (IIr) a hydrogenatom, optionally substituted alkyl or —Z^(a)—R^(10a) is preferable andfurther (IIs) a hydrogen atom or —Z^(a)—R^(10a) is more preferable.

In R^(2a) to R^(5a) a preferable group is independent, (Il) above ispreferable and further (Im) above is more preferable, provided that atleast one of R^(1a) to R^(6a) is —Z^(a)—R^(10a).

In R⁷, (IIt) optionally substituted alkyloxy, optionally substitutedalkylthio, optionally substituted cycloalkyloxy or optionallysubstituted aryloxy is preferable, and further (IIu) optionallysubstituted alkyloxy or optionally substituted alkylthio is morepreferable.

In R⁸, (Ip) above is preferable and further (Iq) above is morepreferable.

In R⁹, (IIv) optionally substituted alkyloxy is preferable and further(Is) above is more preferable.

In R¹⁰, (IIw) carboxy or alkyloxycarbonyl is preferable and further (Iu)above is more preferable.

In Y, (IIx) a single bond, alkylene or alkenylene is preferable, andfurther (Iy) above is more preferable.

In m, (IIy) 0, 1 or 2 is preferable, and (IIz) 0 or 1 is morepreferable.

In n, (IIh) above is preferable and further (IIi) above is morepreferable.

In p, (IIj) above is preferable and further (IIk) above is morepreferable.

In Z, (IIIa) CH, C(R¹⁴) or N is preferable, and further (IIIb) CH or(IIIc) N is more preferable.

Groups of preferred substituents in the ring A^(a), the ring B^(a),R^(5a), R^(7a) to R^(14a), Z^(a), ma, na and pa of the compound ofgeneral formula (II-a) are shown with (Ia) above to (Id) above, (Il)above to (Im) above, (Ip) above to (Iq) above, (Is) above, (Iu) above,(IIh) above to (IIk) above, (IIt) above to (IIw) above, (IIy) above to(IIz) above and (IIId) to (IIIe). Compounds having possible combinationof them are preferable.

In the ring A^(a), (Ia) above is preferable and further (Ib) above ismore preferable.

In the ring B^(a), (Ic) above is preferable and further (Id) above ismore preferable.

In R^(11a) to R^(14a) a preferable group is independent, (Il) above ispreferable and further (Im) above is more preferable.

In R⁷, (IIt) above is preferable and further (IIu) above is morepreferable.

In R⁸, (Ip) optionally substituted alkyl is preferable and further (Iq)above is more preferable.

In R⁹, (IIv) above is preferable and further (Is) above is morepreferable.

In R¹⁰, (IIw) above is preferable and further (Iu) above is morepreferable.

In m, (IIy) above is preferable and further (IIz) above is morepreferable.

In n, (IIh) above is preferable and further (IIi) above is morepreferable.

In p, (IIj) above is preferable and further (IIk) above is morepreferable.

In R⁵, (IIId) a hydrogen atom or optionally substituted alkyl ispreferable and further (IIIe) a hydrogen atom is more preferable.

EFFECT OF INVENTION

The compounds of the present invention are useful as a therapeuticagent, especially for treating allergic diseases, since they have anexcellent DP receptor antagonistic activity and high safety.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds of the present invention can be prepared by the method A,B or C set forth below. In addition, a racemate or an optical isomer isincluded in structural formulae of (I), (III) to (XI) and (I′).

Method A is set forth below,

wherein the ring A, the ring B, X¹, X², X³, X⁴, X⁵, R⁶, R⁷, R⁸, R⁹, M,Y, L¹, L², m, n and p are the same as 1) before; L^(a) and L^(b) areindependently a halogen atom, a hydroxyl group, methanesulfonyloxy orp-toluenesulfonyloxy; Pa is COOt-Bu.

Step 1 is a process in which a compound of the formula (III) iscondensed with a compound of the formula (IV) to give a compound of theformula (V).

The reaction can be carried out by reacting 1 to 5 equivalents of thecompound (IV) compared to the compound (III) in an inert solvent at 0°C. to 150° C. for 5 minutes to 48 hours.

The reaction may be conducted under the presence of 1 to 5 equivalentsof a base. Examples of the preferable base include sodium hydride,potassium carbonate, sodium carbonate, potassium bicarbonate, sodiumbicarbonate, potassium hydroxide, sodium hydroxide and the like.

Examples of the preferable inert solvent include tetrahydrofuran,N,N-dimethylformamide, dimethylsulfoxide, water and the like, which canbe used alone or as a mixed solvent.

Step 2 is a process in which a compound of the formula (V) isdeprotected under an acidic condition to give a compound of the formula(VI).

The reaction can be carried out by using 1 to 20 equivalents of the acidcompared to the compound (V) in an inert solvent at 0° C. to 150° C. for5 minutes to 48 hours.

Examples of the preferable inert solvent include ethyl acetate,methylene chloride, tetrahydrofuran, N,N-dimethylformamide, methanol,dioxane, water and the like, which can be used alone or as a mixedsolvent.

Step 3 is a process in which a compound of the formula (VI) is condensedwith a compound of the formula (VII), and the product is hydrolyzedunder a basic condition if necessary to give a compound of the formula(I).

The reaction can be carried out by reacting 0.8 to 2 equivalents of thecompound of the formula (VII) compared to the compound (VI) in an inertsolvent at 0° C. to 150° C. for 5 minutes to 48 hours.

Examples of the preferable inert solvent include ethyl acetate,methylene chloride, tetrahydrofuran, N,N-dimethylformamide,dimethylsulfoxide, water and the like, which can be used alone or as amixed solvent.

The reaction may be conducted under the presence of 1 to 5 equivalentsof a base compared to the compound of the formula (VII). Examples of thepreferable base include triethylamine, diisopropylethylamine, pyridine,potassium carbonate, sodium carbonate, cesium carbonate, potassiumbicarbonate, sodium bicarbonate and the like.

Hydrolysis can be conducted in an inert solvent by reacting 1 to 5equivalent(s) of a base compared to the compound of the formula (VII) at0° C. to 150° C. for 5 minutes to 48 hours.

Examples of the preferable inert solvent include tetrahydrofuran,methanol, N,N-dimethylformamide, water and the like, which can be usedalone or as a mixed solvent.

A product of each step, the compound (V), (VI) or (I), can be purifiedin a conventional method such as a column chromatography orre-crystallization etc.

Method B is set forth below,

wherein the ring A, the ring B, X¹, X², X³, X⁴, R⁵, R⁶, R⁷, R⁸, R⁹, M,Y, L¹, L², m, n and p are the same as 1) before; L^(a) and L^(b) is ahalogen atom, a hydroxy group, methanesulfoxy or p-toluenesulfonyloxy;P^(a) is COOt-Bu; the dotted line means a bond or non-bond

Step 1 is a process in which a compound of the formula (VIII) iscondensed with a compound of the formula (IX) under a presence ofNaBH(OCOCH₃)₃ to give a compound of the formula (X).

The reaction can be carried out by reacting 1 to 4 equivalents of thecompound (IX) and 1 to 4 equivalents of NaBH(OCOCH₃)₃ compared to thecompound (VIII) in an inert solvent at 0° C. to 150° C. for 5 minutes to48 hours.

Examples of the preferable inert solvent include acetic acid, water andthe like, which can be used alone or as a mixed solvent.

In addition, dehydrogenation is possible using2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), cesium ammonium nitrate(CAN) and the like in a compound of the formula (VIII) wherein thedotted line means non-bonding.

Step 2 is a process in which a compound of the formula (X) isdeprotected under an acidic condition to give a compound of the formula(XI).

The reaction can be carried out by using 1 to 20 equivalents of the acidcompared to the compound (V) in an inert solvent at 0° C. to 150° C. for5 minutes to 48 hours.

Examples of the preferable inert solvent include ethyl acetate,methylene chloride, tetrahydrofuran, N,N-dimethylformamide, methanol,dioxane, water and the like, which can be used alone or as a mixedsolvent.

Step 3 is a process in which a compound of the formula (XI) is condensedwith a compound of the formula (VII), and the product is hydrolyzedunder a basic condition if necessary to give a compound of the formula(I′).

The reaction can be carried out by reacting 0.8 to 2 equivalents of thecompound of the formula (VII) compared to the compound (VI) in an inertsolvent at 0° C. to 150° C. for 5 minutes to 48 hours.

Examples of the preferable inert solvent include ethyl acetate,methylene chloride, tetrahydrofuran, N,N-dimethylformamide,dimethylsulfoxide, water and the like, which can be used alone or as amixed solvent.

The reaction may be conducted under the presence of 1 to 5 equivalentsof a base. Examples of the preferable base include triethylamine,diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate,cesium carbonate, potassium bicarbonate, sodium bicarbonate and thelike.

Hydrolysis can be conducted in an inert solvent by reacting 1 to 5equivalent(s) of a base compared to the compound of the formula (VII) at0° C. to 150° C. for 5 minutes to 48 hours.

Examples of the preferable inert solvent include tetrahydrofuran,methanol, N,N-dimethylformamide, water and the like, which can be usedalone or as a mixed solvent.

A product of each step, the compound (IX), (X) or (I′) can be purifiedin a conventional method such as a column chromatography orre-crystallization etc.

Method C is set forth below,

wherein the ring A, the ring B, X¹, X², X³, X⁴, R⁵, R⁶, R⁷, R⁸, R⁹, M,Y, L¹, L², n and p are the same as 1) before; L^(a) and L^(b) is ahalogen atom, a hydroxy group, methanesulfoxy or p-toluenesulfonyloxy.

Step 1 is a process in which a compound of the formula (VII) iscondensed with a compound of the formula (XXI) to give a compound of theformula (XXII).

The reaction can be carried out by reacting 0.8 to 2 equivalents of thecompound (VII) compared to the compound (XXI) in an inert solvent at 0°C. to 150° C. for 5 minutes to 48 hours.

Examples of the preferable inert solvent include ethyl acetate,methylene chloride, tetrahydrofuran, N,N-dimethylformamide,dimethylsulfoxide, water and the like, which can be used alone or as amixed solvent.

The reaction may be conducted under the presence of 1 to 5 equivalentsof a base compared to the compound (VII). Examples of the preferablebase include triethylamine, diisopropylethylamine, pyridine, potassiumcarbonate, sodium carbonate, cesium carbonate, potassium bicarbonate,sodium bicarbonate and the like.

Step 2 is a process in which a compound of the formula (III) iscondensed with a compound of the formula (XXII) to give a compound ofthe formula (I).

The reaction can be carried out by reacting 1 to 5 equivalents of thecompound (XXII) compared to the compound (III) in an inert solvent at 0°C. to 150° C. for 5 minutes to 48 hours.

The reaction may be conducted under the presence of 1 to 5 equivalentsof a base. Examples of the preferable base include sodium hydride,potassium carbonate, sodium carbonate, potassium bicarbonate, sodiumbicarbonate, potassium hydroxide, sodium hydroxide and the like.

Examples of the preferable inert solvent include tetrahydrofuran,N,N-dimethylformamide, dimethylsulfoxide, water and the like, which canbe used alone or as a mixed solvent.

Hydrolysis can be conducted in an inert solvent by reacting 1 to 5equivalent(s) of a base compared to the compound of the formula (III) at0° C. to 150° C. for 5 minutes to 48 hours.

A product of each step, the compound (XXII) or (I), can be purified in aconventional method such as a column chromatography orre-crystallization etc.

In addition, when a substituent on the ring A is a fluorine atom in thecompound of the formula (I) or (I′), it can be substituted with R⁷ byreacting with R⁷H in an inert solvent under a basic condition.

The compound of the formula (III) or (VIII) is available from commercialproducts or synthesized compounds. Examples of synthetic methods areshown below, but not limited thereto. Additionally, chemical structuresof the formulae (XII) to (XX) and (XXIV) include a racemate or anoptical isomer.

wherein X¹, X², X³, X⁴, R⁵ and R¹⁰ are the same as 1) before; R^(A) is ahydrogen atom or alkyl; W is a hydrogen atom, an oxygen atom, a sulfuratom or a halogen atom; W¹ is alkylene, alkenylene or alkynylene; W² is—O-alkylene or —S-alkylene.

a) When W is an oxygen atom or a sulfur atom, the compound of theformula (XII) can be reacted with a compound of the formula (XIII) in aninert solvent at 0° C. to 150° C. for 5 minutes to 48 hours to give acompound of the formula (XIV).

Examples of the inert solvent include tetrahydrofuran,N,N-dimethylformamide and the like, which can be used alone or as amixed solvent.

Examples of the preferred base include sodium hydride, potassiumcarbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonateand the like.

b) When W is a halogen atom the compound of the formula (XII) can bereacted with a compound of the formula (XV) in an inert solvent at 0° C.to 150° C. for 5 minutes to 48 hours to give a compound of the formula(XVI).

Examples of the inert solvent include tetrahydrofuran,N,N-dimethylformamide and the like, which can be used alone or as amixed solvent.

The compound of the formula (VII) is available from commercial productsor synthesized compounds. Examples of synthetic methods are shown below,but not limited thereto. Additionally, chemical structures of theformulae (XVII) to (XX) include a racemate or an optical isomer.

c) When W is a hydrogen atom, the compound of the formula (XII) can becondensed with a compound of the formula (XXIII) in an inert solvent(e.g., ether, tetrahydrofuran, N,N-dimethylformamide etc.) at 0° C. to150° C. for 5 minutes to 48 hours and the resulting compound is reactedwith hydrazine hydrate and potassium hydroxide at 0° C. to 150° C. for 5minutes to 48 hours to give a compound of the formula (XXIV).

wherein the ring A, R⁷ and q are the same as 1) before; W³ is a halogenatom.

d) The compound of the formula (XVII) is 1) converted to a SO₃Hderivative by treating with ClSO₃Cl, and 2) followed by chlorination ofthe hydroxy group by the reaction with POCl₃ or PCl₅ to give thecompound of the formula (XVIII).e) The compound of the formula (XIX) is 1) lithiated by n-BuLi, and 2)followed by conversion to a SO₂Li derivative by the reaction with SO₂,and finally 3) reacted with SO₂Cl₂ to give the compound of the formula(XX). A bromine atom or an iodine atom is preferable as W³.

In this specification, a term of “solvate” includes, for example, asolvate with an organic solvent, a hydrate and the like. In a case offorming the solvate with an organic solvent, any number of molecules ofthe organic solvent may be coordinated. In a case of forming thehydrate, any number of water molecules may be coordinated. A hydrate isusually preferred.

A term of “compound of the present invention” includes apharmaceutically acceptable salt and a solvate thereof. Examples of thesalt include salts with alkaline metal (lithium, sodium and potassiumetc.), alkaline earth metal (magnesium and calcium etc.), ammonium,organic bases and amino acids and salts with inorganic acids(hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid,etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaricacid, benzenesulfonic acid and p-toluenesulfonic acid etc.). These saltscan be formed by the usual method.

A compound of the present invention is not limited to the specifiedisomer but includes all possible isomers and racemates.

A compound of the present invention shows an excellent DP receptorantagonistic activity as described in the following examples.Accordingly, a pharmaceutical composition of the present invention canbe used as a therapeutic agent for preventing and/or treating allergicdiseases such as asthma, allergic rhinitis, allergic dermatitis,allergic conjunctivitis, food allergy and the like; systemicmastocytosis; systemic disorder of mastcell-activation; lung emphysema;chronic bronchitis; chronic obstructive lung disease; skin disordercharacterized by pruritus such as atopic dermatitis and hives; diseasesoccurring secondarily due to behavior accompanied by pruritus such ascataract and retinal detachment; brain damages such as cerebrovasculardisorder, degenerative brain disorder and demyelinating disease;sleep-waking disorder; Churg-Strauss syndrome; papular dermatitis suchas filariasis; vasculitis; polyarteritis; cutaneous eosoiophilicgranuloma; autoimmune diseases such as multiple sclerosis and transplantrejection; eosoiophilic pneumonopathy; histiocytosis; pneumonia;aspergillosis; pleurisy; sarcoidosis; pulmonary fibrosis; eosinophilia;skin flush such as face flush by nicotinic acid; filariasis;schistosomiasis; trichinelliasis; coccidioidomycosis; tuberculosis;bronchial cancer; lymphoma; Hodgkin's disease and the like.

When a compound of the present invention is administered to a human inorder to treat the diseases above, oral administration through a powder,granule, tablet, capsule, pill, liquid formulation and the like, orparenteral administration through an injection, suppository, transdermalformulation, inhalant and the like is possible.

A pharmaceutical composition can be obtained by mixing a therapeuticallyeffective amount of a compound of the present invention with apharmaceutical additives such as an excipient, binder, wetting agent,disintegrating agent, lubricant and the like, which is suitable to theselected formulation. An injection can be formulated by sterilizationtogether with a suitable carrier.

In the treatment of the diseases related to PGD2 receptor above, it ispossible to use the compound of the present invention combined with orin a coupled formulation with the other therapeutic agent. In the caseof treating inflammatory diseases including allergy, the compound can beused combined with or in a coupled formulation with leukotriene receptorantagonist (e.g., montelukast sodium, zafirlukast, pranlukast hydrate,leukotriene B4 receptor antagonist); leukotriene synthesis inhibitorsuch as zileuton, PDE IV inhibitor (e.g., theophylline, cilomilast,roflumilast), corticosteroid (e.g., prednisolone, fluticasone,budesonide, ciclesonide), β2-agonist (e.g., salbutamol, salmeterol,formoterol), anti IgE antibody (e.g., omalizumab), histamine H1 receptorantagonist (e.g., chlorpheniramine, loratadine, cetirizine),immunosuppressant (tacrolimus, cyclosporin), thromboxane A2 receptorantagonist (e.g., ramatroban), chemokine receptor (especially CCR-1,CCR-2, CCR-3) antagonist, other prostanoid receptor antagonist (e.g.,CRTH2 antagonist), adhesion molecule antagonist (e.g., VLA-4antagonist), cytokine antagonist (e.g., anti-IL-4 antibody, anti-IL-3antibody), Non-steroidal anti-inflammatory agent (e.g., propionic acidderivative such as ibuprofen, ketoprofen and naproxen etc.; acetic acidderivative such as indomethacin, and diclofenac etc.; salicylic acidsuch as acetyl salicylic acid; cyclooxigenase-2 inhibitor such ascelecoxib and etoricoxib).

Further, uses combined with or in a coupled formulation with antitussiveagent (e.g., codein, hydrocodein), cholesterol lowering agent(lovastatin, simvastatin, fluvastatin. rosuvastatin), anticholinergicdrug (e.g., tiotropium, ipratropium, flutropium, oxitropium) are alsopossible.

Dose of the compounds of the present invention depends on condition ofdiseases, route of administration, age and body weight of a patient. Inthe case of oral administration to an adult, the dose range is usually0.1 to 100 mg/kg/day, preferably 1 to 20 mg/kg/day.

Examples

The present invention is illustrated more in detail below by examplesand test examples, but not limited to these examples.

In examples, the following abbreviations are used;

Me: methylBOC: tert-butoxycarbonylDDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DMAP: N,N-dimethylaminopyridine

THF: tetrahydrofuran

DMF: N,N-dimethylformamide MeOH: Methanol Example 1 Preparation of thecompound I-9

Step 1

Oxalyl chloride (5.03 g, 39.6 mmol) was added to a solution of thecompound (1) (5.0 g, 33.0 mmol) in diethyl ether (40 mL) at 0° C. andstirred at the same temperature for 15 minutes. A saturated aqueoussolution of sodium bicarbonate (60 mL) and THF (10 mL) were added to thereaction solution and heated to reflux. The reaction solution was cooledand adjusted to pH 2-3 by adding diluted hydrochloric acid. Theresulting crystalline was collected by filtration, washed with water anddried to give the compound (2) (3.55 g, 48% yield).

Step 2

Hydrazine monohydrate (2.2 mL) and potassium hydroxide (5.29 g, 94.2mmol) were added to the compound (2) (3.55 g, 15.7 mmol) and stirred at180° C. for 3 hours and 40 minutes. The reaction solution was cooled,water (50 mL) and chloroform (20 mL) were added and the mixture wasextracted. After the obtained aqueous layer was adjusted to pH 1-2 byadding diluted hydrochloric acid, the mixture was extracted with diethylether (100 mL) and the organic layer was washed with water and dried.The organic layer was concentrated and the resulting residue [thecompound (2)] was used in the next step without further purification.

Step 3

2,2-Dimethoxypropane (20 mL) and concentrated hydrochloric acid (2 mL)were added to the residue obtained in Step 2 and stirred under heatingat 50° C. for 10 minutes. After the reaction solution was cooled, thereaction solution was extracted with ethyl acetate and the organic layerwas washed with water, a saturated aqueous solution of sodiumbicarbonate and saturated brine successively, dried and concentrated.The resulting residue was purified by a silica gel column chromatography(hexane:ethyl acetate=5:1) and the beluent was concentrated to give aoily compound (3) (3.22 g, 91.7% yield).

¹H-NMR (CDCl₃) δ ppm: 3.71 (s, 3H), 3.83 (s, 2H), 7.03-7.10 (m, 2H),7.25 (d, J=1.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 8.22 (brs, 1H).

Step 4

After diluted hydrochloric acid (2 mL) was added to a solution of thecompound (3) (3.2 g, 14.3 mmol) in MeOH (20 mL), BH₃-pyridine (10.1 mL,100 mmol) was added at 0° C. and the mixture was stirred at the sametemperature for 40 minutes, further at room temperature for 30 minutes.The reaction solution was diluted with water (50 mL) and extracted withdiethyl ether (50 mL). The obtained aqueous layer was adjusted to pH 7-8by adding sodium hydroxide and extracted with ethyl acetate (50 mL). Theorganic layer was washed with water, dried and concentrated to give theoily compound (5) (2.08 g, 64.4% yield).

Step 5

1-(tert-Butoxycarbonyl)-4-piperidone (1.39 g, 6.98 mmol) and sodiumtriacetoxyhydroborate (1.48 g, 6.98 mmol) were added to a solution ofthe compound (5) (1.39 g, 4.65 mmol) in acetic acid (6 mL) and stirredat room temperature for 1 hour. The reaction solution was diluted withwater, extracted with ethyl acetate, and the organic layer was washedwith a saturated aqueous solution of sodium bicarbonate and watersuccessively, dried and concentrated. The resulting residue was purifiedby a silica gel column chromatography (hexane:ethyl acetate=10:1) andthe eluent was concentrated to give the residue [the compound (6)],which was directly used in the next step without further purification.

Step 6

A solution of DDQ (1.11 g) in THF (3 mL) was added to a solution of theresidue [the compound (6)] obtained in Step 5 in THF (5 mL) at 0° C. andstirred at room temperature for 18 hours. A saturated aqueous solutionof sodium bicarbonate (15 mL) was added to the reaction solution,extracted with ethyl acetate (35 mL) and the organic layer was washedwith water, dried and concentrated. The resulting residue was purifiedby a silica gel column chromatography (hexane:ethyl acetate=6:1), theeluent was concentrated and the residue was crystallized fromhexane-ethyl acetate to give the compound (7) (1.6 g, 84% yield).

Step 7

A 4N solution of hydrochloric acid in ethyl acetate (4 mL) was added toa solution of the compound (7) (1.59 g, 3.91 mmol) in ethyl acetate (4mL) and stirred at room temperature for 2 hours. n-Hexane (6 mL) wasadded to the reaction solution and the precipitated crystalline wascollected by filtration to give the compound (8) (1.22 g, 91% yield).

¹H-NMR (DMSO-d₆) δ p pm:2.06-2.27 (m, 4H), 3.04-3.44 (m, 4H), 3.61 (s,3H), 3.78 (s, 2H), 4.72 (m, 1H), 7.06 (dd, J=1.8, 8.4 Hz, 1H), 7.34 (s,1H), 7.51 (d, J=8.4 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 9.19 (brs, 1H).

Step 8

4-Isopropyloxybenzenesulfonylchloride (258 mg, 1.1 mmol) andtriethylamine (0.42 mL) were added to a solution of the compound (8)(343 mg, 1.0 mmol) in THF (3 mL) and stirred at room temperature for 18hours. Water (10 mL) was added to the reaction solution, extracted withethyl acetate and the extract was washed with a saturated brine driedand concentrated. The resulting residue was purified by a silica gelcolumn chromatography (hexane:ethyl acetate=4:1). The eluent wasconcentrated and the residue was crystallized from hexane-ethyl acetateto give the compound (9) (405 mg, 80% yield).

Step 9

The compound (9) (405 mg, 0.8 mmol) was dissolved in MeOH (2.0 mL)-THF(2.0 mL). A 4N aqueous solution of sodium hydroxide (0.5 mL, 2.0 mL) wasadded thereto and stirred at room temperature for 18 hours. After thereaction solution was diluted with water and acidified by adding dilutedhydrochloric acid, the mixture was extracted with ethyl acetate and theextract was washed with water, dried and concentrated. The residue wascrystallized from hexane-ethyl acetate to give the compound I-9 (422 mg,99% yield).

¹H-NMR (DMSO-d₆) δ ppm: 1.33 (d, 6H, J=6.0 Hz), 1.91-1.99 (m, 4H), 3.33(br, 2H), 3.61 (s, 2H), 3.76 (d, 2H, J=12.0 Hz), 4.44 (m, 1H), 4.77 (m,1H), 7.00 (dd, 1H, J=6.6 Hz, 1.8 Hz), 7.17 (d, 2H, 9.3 Hz), 7.42 (s,1H), 7.47 (d, 2H, 8.7 Hz), 7.65-7.71 (m, 3H), 12.26 (br. 1H).

Example 2 Preparation of the compound I-18

Step 1

4-Isopropyloxybenzenesulfonylchloride (5.9 g, 25.4 mmol) andtriethylamine (8.4 mL) were added to a solution of (R)-pyrrolidinehydrochloride (10) (3.0 g, 24.2 mmol) in a mixture of THF (20 mL)-DMF(10 mL) and the mixture was stirred at 0° C. for 5 hours. Water (20 mL)was added to the reaction solution and extracted with ethyl acetate (40mL). The organic layer was washed with diluted hydrochloric acid andwater successively, dried and concentrated. The resulting residue[thecompound (2)] was directly used in the next step without furtherpurification.

Step 2

p-Toluenesulfonylchloride (6.9 g, 36.3 mmol) and DMAP (295 mg, 2.4 mmol)were added to a solution of the compound (2) (6.9 g, 24.2 mmol) inpyridine (20 mL) and stirred at room temperature for 18 hours. Water (30mL) was added to the reaction solution and extracted with ethyl acetate(60 mL). The organic layer was washed with diluted hydrochloric acid andwater successively, dried and concentrated. The resulting residue waspurified by a silica gel column chromatography (hexane:ethylacetate=4:1), the eluent was concentrated and the residue wascrystallized from hexane-ethyl acetate to give the compound (3) (8.28 g,78% yield).

¹H-NMR (CDCl₃) δ ppm: 1.38 (d, J=6.3 Hz, 6H), 1.95-2.04 (m, 2H), 2.46(s, 3H), 3.17-3.49 (m, 4H), 4.64 (m, 1H), 4.94 (m, 1H), 6.94 (d, J=8.7Hz, 2H), 7.33 (d, J=8.7 Hz, 1H), 7.64-7.70 (m, 4H).

Step 3

NaH (60%) (47 mg, 1.17 mmol) was added at 0° C. to a solution ofindole-3-acetic acid methyl ester (200 mg, 1.05 mmol) in DMF (1.5 mL)and stirred for 30 minutes. To the reaction solution, was added asolution of the compound (3) (697 mg, 1.58 mmol) in DMF (4.5 mL) andstirred at 80° C. for 18 hours. After the reaction solution was cooled,water (10 mL) was added and extracted with ethyl acetate (20 mL). Theorganic layer was washed with diluted hydrochloric acid and watersuccessively, dried and concentrated. The resulting residue was purifiedby a silica gel column chromatography (hexane:ethyl acetate=3:1) and theeluent was concentrated to give the compound (4) (117 mg, 24% yield).

Step 4

The compound (4) (170 mg, 0.37 mmol) was dissolved in MeOH (1.5 mL)-THF(1.5 mL). A 4M aqueous solution of sodium hydroxide (0.23 mL, 0.93 mmol)was added and the mixture was stirred at room temperature for 18 hours.After the reaction solution was diluted with water and acidified byadding diluted hydrochloric acid, the mixture was extracted with ethylacetate and the extract was washed with water, dried and concentrated.The residue was crystallized from hexane-ethyl acetate to give thecompound I-18 (132 mg, 80% yield).

¹H-NMR (DMSO-d₆) δ ppm: 1.32 (d, 6H, J=5.7 Hz), 2.12 (m, 1H), 2.28 (m,1H), 3.24-3.67 (m, 6H), 4.76 (m, 1H), 5.06 (m, 1H), 7.00-7.14 (m, 5H),7.35 (d, 1H, J=8.1 Hz), 7.38 (d, 1H, J=7.8 Hz), 7.74 (d, 2H), 12.20 (br,1H).

The compounds I-1 to I-8, I-10 to I-17 and I-19 to I-37 were prepared inthe same manner as described above. The structures and physicalproperties were shown in Table 1-7.

TABLE 1 Compound No. Structure ¹H-NMR δ ppm I-1

(DMSO-d6) 1.33 (d, 6H, J = 6.0 Hz), 1.93- 1.99 (m, 4H), 3.34 (br, 2H),3.61 (s, 2H), 3.78 (d, 2H, J = 11.4 Hz), 4.41 (m, 1H), 4.77 (d, 1H),6.98 (m, 1H,), 7.06 (m, 1H), 7.16 (m, 2H), 7.35 (s, 1H), 7.46 (dd, 2H,7.5 Hz), 7.71 (d, 2H), 12.19 (br, 1H) I-2

(DMSO-d6) 1.38 (dd, 3H, J = 6.9 Hz), 1.93- 1.99 (m, 4H), 3.34 (br, 2H),3.61 (s, 2H), 3.78 (d, 2H, J = 11.1 Hz), 4.15 (dd, 2H), 4.39 (m, 1H),6.98 (m, 1H), 7.07 (m, 1H), 7.18 (d, 2H), 7.35 (s, 1H), 7.46 (dd, 2H,8.7 Hz), 7.72 (d, 2H), 12.18 (br, 1H) I-3

(DMSO-d6) 1.93-2.01 (m, 4H), 3.34 (s, 2H), 3.61 (s, 2H), 3.78 (d, 2H, J= 11.7 Hz), 3.88 (ds, 3H), 4.40 (m, 1H), 6.98 (m, 1H), 7.07 (m, 1H),7.20 (m, 2H), , 7.36 (s, 1H), 7.46 (dd, 2H, 9.0 Hz), 7.73 (d, 2H), 12.18(br, 1H) I-4

(DMSO-d6) 1.96-2.02 (m, 4H), 3.34 (br, 2H), 3.62 (s, 2H), 3.82 (d, 2H, J= 11.7 Hz), 4.42 (m, 1H), 6.98 (m, 1H,), 7.07 (m, 1H), 7.36 (s, 1H),7.42-7.58 (m, 4H), 7.85-7.91 (m, 2H), 12.19 (br, 1H) I-5

(DMSO-d6) 1.33 (d, 6H, J = 5.7 Hz), 1.97 (br, 4H), 3.33 (br, 2H), 3.61(s, 2H), 3.76 (d, 2H, J = 12.3 Hz), 4.42 (m, 1H), 4.77 (m, 1H), 7.07 (d,1H, J = 8.7 Hz), 7.17 (d, 2H, J = 8.1 Hz), 7.45-7.52 (m, 3H), 7.70 (d,2H, J = 8.1 Hz), 12.23 (br, 1H) I-6

(DMSO-d6) 1.38 (dd, 3H, J = 6.9 Hz), 1.93- 1.99 (m, 4H), 3.33 (br, 2H),3.62 (s, 2H), 3.78 (d, 2H, J = 11.7 Hz), 4.13 (dd, 2H), 4.41 (m, 1H),7.07 (dd, 1H, J = 8.7 Hz, 1.8 Hz), 7.18 (d, 2H, 8.7 Hz), 7.45-7.52 (m,3H), 7.72 (d, 2H, 9.0 Hz), 12.23 (br, 1H)

TABLE 2 Compound No. Structure ¹H-NMR δ ppm I-7 

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.12 (m, 1H), 2.28 (m, 1H),3.25-3.33 (m, 3H), 3.43-3.58 (m, 3H), 4.75 (m 1H), 5.08 (m, 1H),7.10-7.19 (m, 4H), 7.41 (d, 1H, J = 9.0 Hz), 7.53 (dd, 1H), 7.73 (d, 2H,J = 8.4 Hz), 12.26 (br, 1H) I-8 

(DMSO-d6) 1.38 (dd, 3H, J = 6.9 Hz), 2.11 (m, 1H), 2.28 (m, 1H),3.23-3.33 (m, 3H), 3.42-3.60 (m, 3H), 4.14 (dd, 2H), 5.08 (m, 1H),7.11-7.15 (m, 4H), 7.42 (d, 1H, J = 8.7 Hz), 7.53 (d, 1H, J = 1.8 Hz),7.74 (d, 2H, J = 9.0 Hz), 12.26 (br, 1H) I-9 

(DMSO-d6) 1.33 (d, 6H, J = 6.0 Hz), 1.91- 1.99 (m, 4H), 3.33 (br, 2H),3.61 (s, 2H), 3.76 (d, 2H, J = 12.0 Hz), 4.44 (m, 1H), 4.77 (m, 1H),7.00 (dd, 1H, J = 6.6 Hz, 1.8 Hz), 7.17 (d, 2H, 9.3 Hz), 7.42 (s, 1H),7.47 (d, 2H, 8.7 Hz), 7.65-7.71 (m, 3H), 12.26 (br, 1H) I-10

(DMSO-d6) 1.38 (dd, 3H, J = 6.9 Hz), 1.93- 1.99 (m, 4H), 3.33 (br, 2H),3.61 (s, 2H), 3.78 (d, 2H, J = 11.1 Hz), 4.15 (dd, 2H), 4.42 (m, 1H),7.00 (dd, 1H, J = 8.1 Hz, 2.1 Hz), 7.19 (d, 2H, 9.0 Hz), 7.42 (s, 1H),7.47 (d, 2H, 8.4 Hz), 7.65-7.71 (m, 3H), 12.24 (br, 1H) I-11

(DMSO-d6) 1.32 (d, 6H, J = 6.3 Hz), 2.08 (m, 1H), 2.28 (m, 1H),3.22-3.30 (m, 3H), 3.43-3.58 (m, 3H), 4.76 (m 1H), 5.09 (m, 1H), 7.05(dd, 1H, J = 6.6 Hz, 1.8 Hz), 7.10- 7.15 (m, 3H), 7.48 (d, 1H, J = 8.4Hz), 7.55 (d, 1H, J = 1.8 Hz), 7.74 (d, 2H, J = 8.7 Hz), 12.26 (br, 1H)I-12

(DMSO-d6) 1.38 (d, 3H, J = 6.9 Hz), 2.09 (m, 1H), 2.27 (m, 1H),3.22-3.30 (m, 3H), 3.42-3.59 (m, 3H), 4.14 (dd, 2H), 5.10 (m 1H), 7.05(dd, 1H, J = 8.4 Hz, 1.8 Hz), 7.07- 7.14 (m, 3H), 7.48 (d, 1H, J = 8.4Hz), 7.54 (d, 1H, J = 1.8 Hz), 7.75 (d, 2H, J = 8.7 Hz), 12.24 (br, 1H)

TABLE 3 Compound No. Structure ¹H-NMR δ ppm I-13

(DMSO-d6) 1.36 (d, 6H, J = 6.0 Hz), 1.99 (br, 4H), 3.33 (br, 2H), 3.62(s, 2H), 3.79 (d, 2H, J = 11.1 Hz), 4.46 (m, 1H), 5.37 (d, 1H), 7.01 (d,1H, J = 8.4 Hz), 7.44 (s, 1H), 7.48 (d, 2H, J = 5.7 Hz), 7.63 (s, 1H),8.04 (dd, 1H), 8.57 (d, 1H), 12.23 (br, 1H) I-14

(DMSO-d6) 1.33 (d, 6H, J = 4.0 Hz), 1.97- 2.10 (m, 4H), 2.44-2.51 (m,4H), 3.60 (s, 2H), 3.78 (d, 2H, J = 7 Hz), 4.42 (m, 1H,), 4.75-4.79 (m,1H), 6.89-6.95 (m, 1H), 7.65- 7.19 (d, 2H, J = 6 Hz), 7.21-7.24 (m, 1H),7.47-7.48 (m, 1H), 7.71 (d, 2H, J = 6 Hz) I-15

(CDCl3) 1.39 (d, 6H, J = 4.0 Hz), 2.16-2.30 (m, 1H), 2.32-2.34 (m, 1H),3.43-3.56 (m, 4H), 3.65-3.76 (m, 2H), 4.63-4.67 (m, 1H), 4.86-4.88 (m,1H), 6.95 (m, 2H), 6.97 (d, 2H, J = 6 Hz), 7.11-7.12 (1H, m), 7.12 (d,1H, J = 8 Hz), 7.75 (d, 2H, J = 6 Hz) I-16

(CDCl3) 1.40 (d, 6H, J = 4.0 Hz), 2.06-2.12 (m, 6H), 2.43-2.49 (m, 2H),3.75 (s, 2H), 3.99 (d, 3H, J = 7 Hz), 4.64-4.68 (m, 1H), 6.89 (d, 2H, J= 7 Hz), 7.00 (d, 2H, J = 5 Hz), 7.09 (s, 1H), 7.47-7.51 (m, 1H), 7.72(d, 2H, J = 5 Hz) I-17

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.16 (m, 1H), 2.31 (m, 1H),3.22-3.64 (m, 6H), 4.75 (m, 1H), 5.12 (m, 1H), 7.09-7.15 (m, 3H), 7.41(s, 1H), 7.48 (d, 1H, J = 8.4 Hz), 7.73 (d, 2H, J = 9.0 Hz), 7.82 (dd,2H, J = 8.1 Hz, 0.9 Hz), 8.32 (dd, 1H, J = 4.5 Hz) I-18

(DMSO-d6) 1.32 (d, 6H, J = 5.7 Hz), 2.12 (m, 1H), 2.28 (m, 1H),3.24-3.67 (m, 6H), 4.76 (m 1H), 5.06 (m, 1H), 7.00-7.14 (m, 5H), 7.35(d, 1H, J = 8.1 Hz), 7.38 (d, 1H, J = 7.8 Hz), 7.74 (d, 2H), 12.20 (br,1H)

TABLE 4 Compound No. Structure ¹H-NMR δ ppm I-19

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.16 (m, 1H), 2.31 (m, 1H),3.24-3.64 (m, 6H), 4.75 (m 1H), 5.12 (m, 1H), 7.09-7.15 (m, 3H), 7.41(s, 1H), 7.72 (d, 2H, J = 8.7 Hz), 7.82 (dd, 1H, J = 8.4 Hz, 1.2 Hz),8.32 (dd, 1H, J = 4.5 Hz). I-20

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.11 (m, 1H), 2.28 (m, 1H),3.24-3.61 (m, 6H), 4.76 (m 1H), 5.06 (m, 1H), 7.00-7.14 (m, 6H), 7.36(d, 2H, J = 8.1 Hz), 7.48 (d, 1H, J = 7.5 Hz), 7.74 (d, 2H, J = 9.0 Hz).I-21

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.16- 2.32 (m, 2H), 3.34-3.51 (m,3H), 3.69 (dd, 1H, J = 10.5, 6.9 Hz), 3.78 (d, 2H), 4.73 (m, 1H), 5.35(m, 1H), 7.06 (d, 2H), 7.39 (dd, 1H, J = 8.7, 1.8 Hz), 7.64-7.68 (m,3H), 7.75 (d, 1H), 12.53 (br, 1H). I-22

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.20- 2.37 (m, 2H), 3.30-3.49 (m,6H), 3.61 (s, 2H), 4.75 (m, 1H), 5.24 (m, 1H), 7.06-7.11 (m, 3H), 7.27(s, 1H), 7.71 (d, 2H, J = 8.7 Hz), 7.91 (d, 1H, J = 8.1 Hz), 8.18 (d,1H, 4.8 Hz), 12.31 (br, 1H). I-23

(DMSO-d6) 1.10 (d, J = 4 Hz, 6H), 1.83- 1.86 (m, 4H), 3.55 (m, 4H), 4.28(m, 1H), 4.52-4.56 (m, 1H), 6.95 (d, J = 5.0 Hz, 4H), 7.36-7.39 (m, 1H),7.48 (d, J = 5.0 Hz, 2H), 7.76-7.78 (m, ,1H), 7.86 (s, ,1H)

TABLE 5 Compound No. Structure ¹H-NMR δ ppm I-24

(DMSO-d6) 1.33 (d, 6H, J = 6.0 Hz), 1.97- 2.04 (m, 4H), 2.48-2.57 (m,2H), 3.78 (d, 2H, J = 10.8 Hz), 4.40 (m, 1H), 4.72 (s, 2H), 4.77 (m,1H), 6.37 (d, 1H, J = 7.5 Hz), 6.46 (3, 1H, J = 3.0 Hz), 6.95 (dd, 1H, J= 8.4 Hz), 7.11 (d, 1H), 7.17 (d, 2H, J = 9.0 Hz), 7.38 (d, 1H, J = 3.3Hz), 7.70 (d, 2H), 12.97 (br, 1H). I-25

(DMSO-d6) 1.98-2.05 (m, 4H), 2.44-2.51 (m, 2H), 3.79 (d, 2H, J = 11.7Hz), 3.88 (s, 3H), 4.39 (m, 1H), 4.73 (s, 2H), 6.37 (d, 1H, J = 7.5 Hz),6.46 (3, 1H, J = 3.0 Hz), 6.95 (dd, 1H, J = 8.1 Hz), 7.10 (d, 1H), 7.21(d, 2H, J = 9.0 Hz), 7.39 (d, 2H), 7.74 (d, 2H), 12.95 (br, 1H). I-26

(DMSO-d6) 1.97-2.04 (m, 4H), 2.49-2.57 (m, 2H), 3.82 (d, 2H, J = 12.0Hz), 4.41 (m, 1H), 4.73 (s, 2H), 6.37 (d, 1H, J = 7.5 Hz), 6.46 (3, 1H,J = 3.3 Hz), 6.96 (dd, 1H, J = 8.1 Hz), 7.09 (d, 1H), 7.39 (d, 1H), 7.35(dd, 2H, J = 9.0 Hz), 7.88 (d, 1H), 12.98 (br, 1H). I-27

(CDCl3) 1.39 (d, J = 4 Hz, 6H), 2.11-2.17 (m, 1H), 2.27-2.33 (m, 1H),2.70 (t, J = 5 Hz, 2H), 3.03 (t, J = 5 Hz, 2H), 3.40-3.49 (m, 1H),3.49-3.54 (m, 1H), 3.66-3.71 (m, 1H), 4.63- 4.67 (m, 1H), 4.89-4.93 (m,1H), 6.82 (s, 1H), 6.98 (d, J = 6 Hz, 2H), 7.1-7.13 (m, 1H), 7.20 (s,2H), 7.57 (d, J = 5 Hz, 1H), 7.76 (d, J = 6 Hz, 2H) I-28

(DMSO-d6) 1.34 (d, 6H, J = 6.0 Hz), 1.76 (d, 2H, J = 9.9 Hz), 2.34 (ddd,2H), 2.58 (dd, 2H, J = 7.8 Hz), 2.67 (dd, 1H), 2.94 (dd, 2H), 3.86 (d,2H, 11.4 Hz), 4.36 (m, 1H), 4.78 (m, 1H), 6.15 (s, 1H), 6.78 (ddd, 1H, J= 12.0, 9.3, 3.0 Hz), 7.18 (m, 4H), 7.75 (d, 2H, J = 9.0 Hz), 12.29 (br,1H).

TABLE 6 Compound No. Structure ¹H-NMR δ ppm I-29

(DMSO-d6) 1.39 (t, 6H, J = 6.9 Hz), 1.77 (d, 2H, J = 11.7 Hz), 2.34(ddd, 2H), 2.58 (dd, 2H, J = 7.8 Hz), 2.65 (dd, 1H), 2.94 (dd, 2H), 3.86(d, 2H, 11.4 Hz), 4.16 (dd, 2H), 4.35 (m, 1H), 6.15 (s, 1H), 6.78 (ddd,1H, J = 12.0, 9.3, 3.0 Hz), 7.17-7.21 (m, 4H), 7.77 (d, 2H, J = 9.0 Hz),12.25 (br, 1H). I-30

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.16- 2.32 (m, 2H), 3.34-3.51 (m,3H), 3.69 (dd, 1H, J = 10.5, 6.9 Hz), 3.78 (d, 2H), 4.73 (m, 1H), 5.35(m, 1H), 7.06 (d, 2H), 7.39 (dd, 1H, J = 8.7, 1.8 Hz), 7.64-7.68 (m,3H), 7.75 (d, 1H), 12.53 (br, 1H). I-31

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.03- 2.35 (m, 2H), 3.22-3.56 (m,6H), 4.75 (m, 1H), 5.03 (m, 1H), 6.89 (dd, 1H, J = 7.8 Hz), 7.10-7.13(m, 3H), 7.28 (d, 1H, J = 8.7 Hz), 7.47 (dd, 1H), 7.74 (d, 2H, J = 8.4Hz), 12.25 (br, 1H). I-32

(CDCl3-d6) 1.38 (d, 6H, J = 6.3 Hz), 2.25- 2.49 (m, 2H), 3.45-3.60 (m,3H), 3.75 (d, 1H, J = 10.8 Hz, 6.6 Hz), 4.65 (m, 1H), 4.89 (m, 1H), 6.96(d, 2H, J = 9.0 Hz), 7.27-7.31 (m, 2H), 7.74 (d, 2H), 7.84 (s, 1H), 8.12(d, 1H, J = 8.4 Hz) I-33

(CDCl3-d6) 1.38 (d, 6H, J = 6.3 Hz), 2.25- 2.50 (m, 2H), 3.45-3.63 (m,3H), 3.75 (d, 1H, J = 11.1 Hz, 6.9 Hz), 4.65 (m, 1H), 4.86 (m, 1H),6.94-7.10 (m, 4H), 7.74 (d, 2H, J = 6.9 Hz), 7.83 (s, 1H), 8.14 (dd, 1H,J = 9.0 Hz, 5.4 Hz).

TABLE 7 Compound No. Structure ¹H-NMR δ ppm I-34

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.11- 2.35 (m, 2H), 3.23-3.61 (m,4H), 4.74-4.81 (m, 3H), 5.03 (m, 1H), 6.41 (m, 2H), 7.00 (m, 2H),7.11-7.14 (m, 3H), 7.73 (d, 8.7 Hz). I-35

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.14- 2.40 (m, 2H), 3.21-3.56 (m,4H), 3.79 (s, 3H), 4.74 (m, 1H), 5.11 (m, 1H), 6.85 (dd, 1H, J = 9.0 Hz,1.8 Hz), 7.08-7.11 (m, 3H), 7.72 (d, 2H, J = 9.0 Hz), 7.85 (d, 2H). I-36

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.11- 2.35 (m, 2H), 3.23-3.61 (m,4H), 4.74-4.81 (m, 3H), 5.03 (m, 1H), 6.41 (m, 2H), 7.00 (m, 2H),7.11-7.14 (m, 3H), 7.73 (d, 8.7 Hz). I-37

(DMSO-d6) 1.32 (d, 6H, J = 6.0 Hz), 2.28- 2.36 (m, 2H), 3.21-3.58 (m,4H), 4.74 (m, 1H), 5.14 (m, 1H), 7.09 (d, 2H, J = 9.0 Hz), 7.22 (m, 2H),7.49-7.52 (m, 1H), 7.71 (d, 2H), 7.97 (s, 1H), 8.01-8.03 (m, 1H).

Further, compounds of Tables 8-12 are prepared in the same manner asdescribed above.

TABLE 8 Com- pound No. Structure II-1

II-2

II-3

II-4

II-5

II-6

TABLE 9

II-7 

II-8 

II-9 

II-10

II-11

II-12

TABLE 10 Compound No. Structure II-13

II-14

II-15

II-16

II-17

II-18

TABLE 11 Compound No. Structure II-19

II-20

II-21

II-22

II-23

II-24

TABLE 12 Compound No. Structure II-25

II-26

II-27

II-28

II-29

II-30

Further, a compound of the formula below

wherein —X¹═X²—X³═X⁴— is —C(R¹)═C(R²)—C(R³)═C(R⁴)—,—N—C(R²)—C(R³)═C(R⁴)—, —C(R¹)═N—C(R³)═C(R⁴)—, —C(R¹)═C(R²)—N═C(R⁴)— or—C(R¹)═C(R²)—C(R³)═N—;

X⁵ is —N═ or —C(R⁵)═;

R¹, R², R³, R⁴, R⁵ and R⁶ are independently a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, methyl, trifluoromethyl,methyloxy, difluoromethyloxy, N-methylamino, methylcarbonylamino, cyano,nitro, phenyl, 2-pyridyl, 2-furyl, 1,3-oxazol-2-yl, morpholino,N-methylcarbamoyl, carboxy, carboxymethyl or carboxymethyloxy;

Z is ═N— or ═C(R^(8D))—;

R⁷ is independently methyloxy, ethyloxy, propyloxy, isopropyloxy,n-butyloxy, isopropyloxy, s-butyloxy, difluoromethyloxy, benzyloxy,phenoxy, methylthio, ethylthio, isopropylthio, s-butylthio,difluoromethylthio, benzylthio or phenylthio; and

R^(8A), R^(8B), R^(8C) and R^(8D) are independently a hydrogen atom, afluorine atom, a chlorine atom, a bromine atom or methyl,

is prepared in the same manner as described above.

A combination of —X¹═X²—X³═X⁴—, X⁵ and R⁶ (part A) is shown in Tables13-31. A combination of R^(8A), Z, R^(8B), and R^(8C) (part B) is shownin Tables 32-40.

TABLE 13 No. X1 X2 X3 X4 X5 R6 S-1 C—COOH CH CH CH CH H S-2 CH C—COOH CHCH CH H S-3 CH CH C—COOH CH CH H S-4 CH CH CH C—COOH CH H S-5 CH CH CHCH C—COOH H S-6 CH CH CH CH CH COOH S-7 CH CH CH CH N COOH S-8 C—COOHC—Cl CH CH CH H S-9 CH C—COOH C—C1 CH CH H S-10 CH CH C—COOH C—Cl CH HS-11 CH CH CH C—COOH C—Cl H S-12 CH CH CH CH C—COOH Cl S-13 C—Cl CH CHCH CH COOH S-14 CH C—Cl CH CH CH COOH S-15 CH CH C—Cl CH CH COOH S-16 CHCH C—Cl CH N COOH S-17 CH CH CH C—Cl CH COOH S-18 CH CH CH CH C—Cl COOHS-19 C—COOH C—Me CH CH CH H S-20 CH C—COOH C—Me CH CH H S-21 CH CHC—COOH C—Me CH H S-22 CH CH CH C —COOH C—Me H S-23 CH CH CH CH C—COOH MeS-24 C—Me CH CH CH CH COOH S-25 CH C—Me CH CH CH COOH S-26 CH CH C—Me CHCH COOH S-27 CH CH C—Me CH N COOH S-28 CH CH CH C—Me CH COOH S-29 CH CHCH CH C—Me COOH S-30 C—COOH C—CF3 CH CH CH H S-31 CH C—COOH C—CF3 CH CHH

TABLE 14 No. X1 X2 X3 X4 X5 R6 S-32 CH CH C—COOH C—CF3 CH H S-33 CH CHCH C—COOH C—CF3 H S-34 CH CH CH CH C—COOH CF3 S-35 C—CF3 CH CH CH CHCOOH S-36 CH C—CF3 CH CH CH COOH S-37 CH CH C—CF3 CH CH COOH S-38 CH CHC—CF3 CH N COOH S-39 CH CH CH C—CF3 CH COOH S-40 CH CH CH CH C—CF3 COOHS-41 C—COOH C—OMe CH CH CH H S-42 CH C—COOH C—OMe CH CH H S-43 CH CHC—COOH C—OMe CH H S-44 CH CH CH C—COOH C—OMe H S-45 CH CH CH CH C—COOHOMe S-46 C—OMe CH CH CH CH COOH S-47 CH C—OMe CH CH CH COOH S-48 CH CHC—OMe CH CH COOH S-49 CH CH C—OMe CH N COOH S-50 CH CH CH C—OMe CH COOHS-51 CH CH CH CH C—OMe COOH S-52 C—COOH C—OCHF2 CH CH CH H S-53 CHC—COOH C—OCHF2 CH CH H S-54 CH CH C—COOH C—OCHF2 CH H S-55 CH CH CHC—COOH C—OCHF2 H S-56 CH CH CH CH C—COOH OCHF2 S-57 C—OCHF2 CH CH CH CHCOOH S-58 CH C—OCHF2 CH CH CH COOH S-59 CH CH C—OCHF2 CH CH COOH S-60 CHCH C—OCHF2 CH N COOH S-61 CH CH CH C—OCHF2 CH COOH S-62 CH CH CH CHC—OCHF2 COOH

TABLE 15 No. X1 X2 X3 X4 X5 R6 S-63 C—COOH C—SMe CH CH CH H S-64 CHC—COOH C—SMe CH CH H S-65 CH CH C—COOH C—SMe CH H S-66 CH CH CH C—COOHC—SMe H S-67 CH CH CH CH C—COOH SMe S-68 C—SMe CH CH CH CH COOH S-69 CHC—SMe CH CH CH COOH S-70 CH CH C—SMe CH CH COOH S-71 CH CH C—SMe CH NCOOH S-72 CH CH CH C—SMe CH COOH S-73 CH CH CH CH C—SMe COOH S-74 C—COOHC—SO2Me CH CH CH H S-75 CH C—COOH C—SO2Me CH CH H S-76 CH CH C—COOHC—SO2Me CH H S-77 CH CH CH C—COOH C—SO2Me H S-78 CH CH CH CH C—COOHSO2Me S-79 C—SO2Me CH CH CH CH COOH S-80 CH C—SO2Me CH CH CH COOH S-81CH CH C—SO2Me CH CH COOH S-82 CH CH C—SO2Me CH N COOH S-83 CH CH CHC—SO2Me CH COOH S-84 CH CH CH CH C—SO2Me COOH S-85 C—COOH C—NHMe CH CHCH H S-86 CH C—COOH C—NHMe CH CH H S-87 CH CH C—COOH C—NHMe CH H S-88 CHCH CH C—COOH C—NHMe H S-89 CH CH CH CH C—COOH NHMe S-90 C—NHMe CH CH CHCH COOH S-91 CH C-NHMe CH CH CH COOH S-92 CH CH C—NHMe CH CH COOH S-93CH CH C—NHMe CH N COOH

TABLE 16 No. X1 X2 X3 X4 X5 R6 S-94 CH CH CH C—NHMe CH COOH S-95 CH CHCH CH C—NHMe COOH S-96 C—COOH C—NHCOMe CH CH CH H S-97 CH C—COOHC—NHCOMe CH CH H S-98 CH CH C—COOH C—NHCOMe CH H S-99 CH CH CH C—COOHC—NHCOMe H S-100 CH CH CH CH C—COOH NHCOMe S.101 C—NHCOMe CH CH CH CHCOOH S-102 CH C—NHCOMe CH CH CH COOH S-103 CH CH C—NHCOMe CH CH COOHS-104 CH CH C—NHCOMe CH N COOH S.105 CH CH CH C—NHCOMe CH COOH S-106 CHCH CH CH C—NHCOMe COOH S-107 C—COOH C—CN CH CH CH H S-108 CH C—COOH C—CNCH CH H S-109 CH CH C—COOH C—CN CH H S-110 CH CH CH C—COOH C—CN H S-111CH CH CH CH C—COOH CN S.112 C—CN CH CH CH CH COOH S-113 CH C—CN CH CH CHCOOH S-114 CH CH C—CN CH CH COOH S-115 CH CH C—CN CH N COOH S.116 CH CHCH C—CN CH COOH S-117 CH CH CH CH C—CN COOH S-118 C—COOH C—NO2 CH CH CHH S-119 CH C—COOH C—NO2 CH CH H S-120 CH CH C—COOH C—NO2 CH H S-121 CHCH CH C—COOH C—NO2 H S-122 CH CH CH CH C—COOH NO2 S-123 C—NO2 CH CH CHCH COOH S-124 CH C—NO2 CH CH CH COOH

TABLE 17 No. X1 X2 X3 X4 X5 R6 S-125 CH CH C—NO2 CH CH COOH S-126 CH CHC—NO2 CH N COOH S-127 CH CH CH C—NO2 CH COOH S-128 CH CH CH CH C—NO2COOH S-129 C—COOH C—Ph CH CH CH H S-130 CH C—COOH C—Ph CH CH H S-131 CHCH C—COOH C—Ph CH H S-132 CH CH CH C—COOH C—Ph H S-133 CH CH CH CHC—COOH Ph S-134 C—Ph CH CH CH CH COOH S-135 CH C—Ph CH CH CH COOH S-136CH CH C—Ph CH CH COOH S-137 CH CH C—Ph CH N COOH S-138 CH CH CH C—Ph CHCOOH S-139 CH CH CH CH C—Ph COOH S-140 C—COOH C-2-pyridyl CH CH CH HS-141 CH C—COOH C-2-pyridyl CH CH H S-142 CH CH C—COOH C-2-pyridyl CH HS-143 CH CH CH C—COOH C-2-pyridyl H S-144 CH CH CH CH C—COOH 2-pyridylS-145 C-2-pyridyl CH CH CH CH COOH S-146 CH C-2-pyridyl CH CH CH COOHS-147 CH CH C-2-pyridyl CH CH COOH S-148 CH CH C-2-pyridyl CH N COOHS-149 CH CH CH C-2-pyridyl CH COOH S-150 CH CH CH CH C-2-pyridyl COOHS-151 C—COOH C-2-furyl CH CH CH H S-152 CH C—COOH C-2-furyl CH CH HS-153 CH CH C—COOH C-2-furyl CH H S-154 CH CH CH C—COOH C-2-furyl HS-155 CH CH CH CH C—COOH 2-furyl

TABLE 18 No. X1 X2 X3 X4 X5 R6 S-156 C-2-furyl CH CH CH CH COOH S-157 CHC-2-furyl CH CH CH COOH S-158 CH CH C-2-furyl CH CH COOH S-159 CH CHC-2-furyl CH N COOH S-160 CH CH CH C-2-furyl CH COOH S-161 CH CH CH CHC-2-furyl COOH S-162 C—COOH C-1,3-oxazol-2-yl CH CH CH H S-163 CH C—COOHC-1,3-oxazol-2-yl CH CH H S-164 CH CH C—COOH C-1,3-oxazol-2-yl CH HS-165 CH CH CH C—COOH C-1,3-oxazol-2-yl H S-166 CH CH CH CH C—COOHC-1,3-oxazol-2-yl S-167 C-1,3-oxazol-2-yl CH CH CH CH COOH S-168 CHC-1,3-oxazol-2-yl CH CH CH COOH S-169 CH CH C-1,3-oxazol-2-yl CH CH COOHS-170 CH CH C-1,3-oxazol-2-yl CH N COOH S-171 CH CH CH C-1,3-oxazol-2-ylCH COOH S-172 CH CH CH CH C-1,3-oxazol-2-yl COOH S-173 C—COOHC-morpholino CH CH CH H S-174 CH C—COOH C-morpholino CH CH H S-175 CH CHC—COOH C-morpholino CH H S-176 CH CH CH C—COOH C-morpholino H S-177 CHCH CH CH C—COOH morpholino S-178 C-morpholino CH CH CH CH COOH S-179 CHC-morpholino CH CH CH COOH S-180 CH CH C-morpholino CH CH COOH S-181 CHCH C-morpholino CH N COOH S-182 CH CH CH C-morpholino CH COOH S-183 CHCH CH CH C-morpholino COOH S-184 C—COOH C—CONHMe CH CH CH H S-185 CHC—COOH C—CONHMe CH CH H S-186 CH CH C—COOH C—CONHMe CH H

TABLE 19 No. X1 X2 X3 X4 X5 R6 S-187 CH CH CH C—COOH C—CONHMe H S-188 CHCH CH CH C—COOH CONHMe S-189 C—CONHMe CH CH CH CH COOH S-190 CH C—CONHMeCH CH CH COOH S-191 CH CH C—CONHMe CH CH COOH S-192 CH CH C—CONHMe CH NCOOH S-193 CH CH CH C—CONHMe CH COOH S-194 CH CH CH CH C—CONHMe COOHS-195 C—CH2COOH CH CH CH CH H S-196 CH C—CH2COOH CH CH CH H S-197 CH CHC—CH2COOH CH CH H S-198 CH CH CH C—CH2COOH CH H S-199 CH CH CH CHC—CH2COOH H S-200 CH CH CH CH CH CH2COOH S-201 CH CH CH CH N CH2COOHS-202 C—CH2COOH C—Cl CH CH CH H S-203 CH C—CH2COOH C—Cl CH CH H S-204 CHCH C—CH2COOH C—Cl CH H S-205 CH CH CH C—CH2COOH C—Cl H S-206 CH CH CH CHC—CH2COOH Cl S-207 C—Cl CH CH CH CH CH2COOH S-208 CH C—Cl CH CH CHCH2COOH S-209 CH CH C—Cl CH CH CH2COOH S-210 CH CH C—Cl CH N CH2COOHS-211 CH CH CH C—Cl CH CH2COOH S-212 CH CH CH CH C—Cl CH2COOH S-213C—CH2COOH C—Me CH CH CH H S-214 CH C—CH2COOH C—Me CH CH H S-215 CH CHC—CH2COOH C—Me CH H S-216 CH CH CH C—CH2COOH C—Me H S-217 CH CH CH CHC—CH2COOH Me

TABLE 20 No. X1 X2 X3 X4 X5 R6 S-218 C—Me CH CH CH CH CH2COOH S-219 CHC—Me CH CH CH CH2COOH S-220 CH CH C—Me CH CH CH2COOH S-221 CH CH C—Me CHN CH2COOH S-222 CH CH CH C—Me CH CH2COOH S-223 CH CH CH CH C—Me CH2COOHS-224 C—CH2COOH C—CF3 CH CH CH H S-225 CH C—CH2COOH C—CF3 CH CH H S-226CH CH C—CH2COOH C—CF3 CH H S-227 CH CH CH C—CH2COOH C—CF3 H S-228 CH CHCH CH C—CH2COOH CF3 S-229 C—CF3 CH CH CH CH CH2COOH S-230 CH C—CF3 CH CHCH CH2COOH S-231 CH CH C—CF3 CH CH CH2COOH S-232 CH CH C—CF3 CH NCH2COOH S-233 CH CH CH C—CF3 CH CH2COOH S-234 CH CH CH CH C—CF3 CH2COOHS-235 C—CH2COOH C—OMe CH CH CH H S-236 CH C—CH2COOH C—OMe CH CH H S-237CH CH C—CH2COOH C—OMe CH H S-238 CH CH CH C—CH2COOH C—OMe H S-239 CH CHCH CH C—CH2COOH OMe S-240 C—OMe CH CH CH CH CH2COOH S-241 CH C—OMe CH CHCH CH2COOH S-242 CH CH C—OMe CH CH CH2COOH S-243 CH CH C—OMe CH NCH2COOH S-244 CH CH CH C—OMe CH CH2COOH S-245 CH CH CH CH C—OMe CH2COOHS-246 C—CH2COOH C—OCHF2 CH CH CH H S-247 CH C—CH2COOH C—OCHF2 CH CH HS-248 CH CH C—CH2COOH C—OCHF2 CH H

TABLE 21 No. X1 X2 X3 X4 X5 R6 S-249 CH CH CH C—CH2COOH C—OCHF2 H S-250CH CH CH CH C—CH2COOH OCHF2 S-251 C—OCHF2 CH CH CH CH CH2COOH S-252 CHC—OCHF2 CH CH CH CH2COOH S-253 CH CH C—OCHF2 CH CH CH2COOH S-254 CH CHC—OCHF2 CH N CH2COOH S-255 CH CH CH C—OCHF2 CH CH2COOH S-256 CH CH CH CHC—OCHF2 CH2COOH S-257 C—CH2COOH C—SMe CH CH CH H S-258 CH C—CH2COOHC—SMe CH CH H S-259 CH CH C—CH2COOH C—SMe CH H S-260 CH CH CH C—CH2COOHC—SMe H S-261 CH CH CH CH C—CH2COOH SMe S-262 C—SMe CH CH CH CH CH2COOHS-263 CH C—SMe CH CH CH CH2COOH S-264 CH CH C—SMe CH CH CH2COOH S-265 CHCH C—SMe CH N CH2COOH S-266 CH CH CH C—SMe CH CH2COOH S-267 CH CH CH CHC—SMe CH2COOH S-268 C—CH2COOH C—SO2Me CH CH CH H S-269 CH C—CH2COOHC—SO2Me CH CH H S-270 CH CH C—CH2COOH C—SO2Me CH H S-271 CH CH CHC—CH2COOH C—SO2Me H S-272 CH CH CH CH C—CH2COOH SO2Me S-273 C—SO2Me CHCH CH CH CH2COOH S-274 CH C—SO2Me CH CH CH CH2COOH S-275 CH CH C—SO2MeCH CH CH2COOH S-276 CH CH C—SO2Me CH N CH2COOH S-277 CH CH CH C—SO2Me CHCH2COOH S-278 CH CH CH CH C—SO2Me CH2COOH S-279 C—CH2COOH C—NHMe CH CHCH H

TABLE 22 No. X1 X2 X3 X4 X5 R6 S-280 CH C—CH2COOH C—NHMe CH CH H S-281CH CH C—CH2COOH C—NHMe CH H S-282 CH CH CH C—CH2COOH C—NHMe H S-283 CHCH CH CH C—CH2COOH NHMe S-284 C—NHMe CH CH CH CH CH2COOH S-285 CH C—NHMeCH CH CH CH2COOH S-286 CH CH C—NHMe CH CH CH2COOH S-287 CH CH C—NHMe CHN CH2COOH S-288 CH CH CH C—NHMe CH CH2COOH S-289 CH CH CH CH C—NHMeCH2COOH S-290 C—CH2COOH C—NHCOMe CH CH CH H S-291 CH C—CH2COOH C—NHCOMeCH CH H S-292 CH CH C—CH2COOH C—NHCOMe CH H S-293 CH CH CH C—CH2COOHC—NHCOMe H S-294 CH CH CH CH C—CH2COOH NHCOMe S-295 C—NHCOMe CH CH CH CHCH2COOH S-296 CH C—NHCOMe CH CH CH CH2COOH S-297 CH CH C—NHCOMe CH CHCH2COOH S-298 CH CH C—NHCOMe CH N CH2COOH S-299 CH CH CH C—NHCOMe CHCH2COOH S-300 CH CH CH CH C—NHCOMe CH2COOH S-301 C—CH2COOH C—CN CH CH CHH S-302 CH C—CH2COOH C—CN CH CH H S-303 CH CH C—CH2COOH C—CN CH H S-304CH CH CH C—CH2COOH C—CN H S-305 CH CH CH CH C—CH2COOH CN S-306 C—CN CHCH CH CH CH2COOH S-307 CH C—CN CH CH CH CH2COOH S-308 CH CH C—CN CH CHCH2COOH S-309 CH CH C—CN CH N CH2COOH S-310 CH CH CH C—CN CH CH2COOH

TABLE 23 No. X1 X2 X3 X4 X5 R6 S-311 CH CH CH CH C—CN CH2COOH S-312C—CH2COOH C—NO2 CH CH CH H S-313 CH C—CH2COOH C—NO2 CH CH H S-314 CH CHC—CH2COOH C—NO2 CH H S-315 CH CH CH C—CH2COOH C—NO2 H S-316 CH CH CH CHC—CH2COOH NO2 S-317 C—NO2 CH CH CH CH CH2COOH S-318 CH C—NO2 CH CH CHCH2COOH S-319 CH CH C—NO2 CH CH CH2COOH S-320 CH CH C—NO2 CH N CH2COOHS-321 CH CH CH C—NO2 CH CH2COOH S-322 CH CH CH CH C—NO2 CH2COOH S-323C—CH2COOH C—Ph CH CH CH H S-324 CH C—CH2COOH C—Ph CH CH H S-325 CH CHC—CH2COOH C—Ph CH H S-326 CH CH CH C—CH2COOH C—Ph H S-327 CH CH CH CHC—CH2COOH Ph S-328 C—Ph CH CH CH CH CH2COOH S-329 CH C—Ph CH CH CHCH2COOH S-330 CH CH C—Ph CH CH CH2COOH S-331 CH CH C—Ph CH N CH2COOHS-332 CH CH CH C—Ph CH CH2COOH S-333 CH CH CH CH C—Ph CH2COOH S-334C—CH2COOH C-2-pyridyl CH CH CH H S-335 CH C—CH2COOH C-2-pyridyl CH CH HS-336 CH CH C—CH2COOH C-2-pyridyl CH H S-337 CH CH CH C—CH2COOHC-2-pyridyl H S-338 CH CH CH CH C—CH2COOH 2-pyridyl S-339 C-2-pyridyl CHCH CH CH CH2COOH S-340 CH C-2-pyridyl CH CH CH CH2COOH S-341 CH CHC-2-pyridyl CH CH CH2COOH

TABLE 24 No. X1 X2 X3 X4 X5 R6 S-342 CH CH C-2-pyridyl CH N CH2COOHS-343 CH CH CH C-2-pyridyl CH CH2COOH S-344 CH CH CH CH C-2-pyridylCH2COOH S-345 C—CH2COOH C-2-furyl CH CH CH H S-346 CH C—CH2COOHC-2-furyl CH CH H S-347 CH CH C—CH2COOH C-2-furyl CH H S-348 CH CH CHC—CH2COOH C-2-furyl H S-349 CH CH CH CH C—CH2COOH 2-furyl S-350C-2-furyl CH CH CH CH CH2COOH S-351 CH C-2-furyl CH CH CH CH2COOH S-352CH CH C-2-furyl CH CH CH2COOH S-353 CH CH C-2-furyl CH N CH2COOH S-354CH CH CH C-2-furyl CH CH2COOH S-355 CH CH CH CH C-2-furyl CH2COOH S-356C—CH2COOH C-1,3-oxazol-2-yl CH CH CH H S-357 CH C—CH2COOHC-1,3-oxazol-2-yl CH CH H S-358 CH CH C—CH2COOH C-1,3-oxazol-2-yl CH HS-359 CH CH CH C—CH2COOH C-1,3-oxazol-2-yl H S-360 CH CH CH CH C—CH2COOH1,3-oxazol-2-yl S-361 C-1,3-oxazol-2-yl CH CH CH CH CH2COOH S-362 CHC-1,3-oxazol-2-yl CH CH CH CH2COOH S-363 CH CH C-1,3-oxazol-2-yl CH CHCH2COOH S-364 CH CH C-1,3-oxazol-2-yl CH N CH2COOH S-365 CH CH CHC-1,3-oxazol-2-yl CH CH2COOH S-366 CH CH CH CH C-1,3-oxazol-2-yl CH2COOHS-367 C—CH2COOH C-morpholino CH CH CH H S-368 CH C—CH2COOH C-morpholinoCH CH H S-369 CH CH C—CH2COOH C-morpholino CH H S-370 CH CH CH C—CH2COOHC-morpholino H S-371 CH CH CH CH C—CH2COOH morpholino S-372 C-morpholinoCH CH CH CH CH2COOH

TABLE 25 No. X1 X2 X3 X4 X5 R6 S-373 CH C-morpholino CH CH CH CH2COOHS-374 CH CH C-morpholino CH CH CH2COOH S-375 CH CH C-morpholino CH NCH2COOH S-376 CH CH CH C-morpholino CH CH2COOH S-377 CH CH CH CHC-morpholino CH2COOH S-378 C—CH2COOH C—CONHMe CH CH CH H S-379 CHC—CH2COOH C—CONHMe CH CH H S-380 CH CH C—CH2COOH C—CONHMe CH H S-381 CHCH CH C—CH2COOH C—CONHMe H S-382 CH CH CH CH C—CH2COOH CONHMe S-383C—CONHMe CH CH CH CH CH2COOH S-384 CH C—CONHMe CH CH CH CH2COOH S-385 CHCH C—CONHMe CH CH CH2COOH S-386 CH CH C—CONHMe CH N CH2COOH S-387 CH CHCH C—CONHMe CH CH2COOH S-388 CH CH CH CH C—CONHMe CH2COOH S-389C—OCH2COOH CH CH CH CH H S-390 CH C—OCH2COOH CH CH CH H S-391 CH CHC—OCH2COOH CH CH H S-392 CH CH CH C—OCH2COOH CH H S-393 CH CH CH CHC—OCH2COOH H S-394 CH CH CH CH CH OCH2COOH S-395 CH CH CH CH N OCH2COOHS-396 C—OCH2COOH C—Cl CH CH CH H S-397 CH C—OCH2COOH C—Cl CH CH H S-398CH CH C—OCH2COOH C—Cl CH H S-399 CH CH CH C—OCH2COOH C—Cl H S-400 CH CHCH CH C—OCH2COOH Cl S-401 C—Cl CH CH CH CH OCH2COOH S-402 CH C—Cl CH CHCH OCH2COOH S-403 CH CH C—Cl CH CH OCH2COOH

TABLE 26 No. X1 X2 X3 X4 X5 R6 S-404 CH CH C—Cl CH N OCH2COOH S-405 CHCH CH C—Cl CH OCH2COOH S-406 CH CH CH CH C—Cl OCH2COOH S-407 C—OCH2COOHC—Me CH CH CH H S-408 CH C—OCH2COOH C—Me CH CH H S-409 CH CH C—OCH2COOHC—Me CH H S-410 CH CH CH C—OCH2COOH C—Me H S-411 CH CH CH CH C—OCH2COOHMe S-412 C—Me CH CH CH CH OCH2COOH S-413 CH C—Me CH CH CH OCH2COOH S-414CH CH C—Me CH CH OCH2COOH S-415 CH CH C—Me CH N OCH2COOH S-416 CH CH CHC—Me CH OCH2COOH S-417 CH CH CH CH C—Me OCH2COOH S-418 C—OCH2COOH C—CF3CH CH CH H S-419 CH C—OCH2COOH C—CF3 CH CH H S-420 CH CH C—OCH2COOHC—CF3 CH H S-421 CH CH CH C—OCH2COOH C—CF3 H S-422 CH CH CH CHC—OCH2COOH CF3 S-423 C—CF3 CH CH CH CH OCH2COOH S-424 CH C—CF3 CH CH CHOCH2COOH S-425 CH CH C—CF3 CH CH OCH2COOH S-426 CH CH C—CF3 CH NOCH2COOH S-427 CH CH CH C—CF3 CH OCH2COOH S-428 CH CH CH CH C—CF3OCH2COOH S-429 C—OCH2COOH C—OMe CH CH CH H S-430 CH C—OCH2COOH C—OMe CHCH H S-431 CH CH C—OCH2COOH C—OMe CH H S-432 CH CH CH C—OCH2COOH C—OMe HS-433 CH CH CH CH C—OCH2COOH OMe S-434 C—OMe CH CH CH CH OCH2COOH

TABLE 27 No. X1 X2 X3 X4 X5 R6 S-435 CH C—OMe CH CH CH OCH2COOH S-436 CHCH C—OMe CH CH OCH2COOH S-437 CH CH C—OMe CH N OCH2COOH S-438 CH CH CHC—OMe CH OCH2COOH S-439 CH CH CH CH C—OMe OCH2COOH S-440 C—OCH2COOHC—OCHF2 CH CH CH H S-441 CH C—OCH2COOH C—OCHF2 CH CH H S-442 CH CHC—OCH2COOH C—OCHF2 CH H S-443 CH CH CH C—OCH2COOH C—OCHF2 H S-444 CH CHCH CH C—OCH2COOH OCHF2 S-445 C—OCHF2 CH CH CH CH OCH2COOH S-446 CHC—OCHF2 CH CH CH OCH2COOH S-447 CH CH C—OCHF2 CH CH OCH2COOH S-448 CH CHC—OCHF2 CH N OCH2COOH S-449 CH CH CH C—OCHF2 CH OCH2COOH S-450 CH CH CHCH C—OCHF2 OCH2COOH S-451 C—OCH2COOH C—SMe CH CH CH H S-452 CHC—OCH2COOH C—SMe CH CH H S-453 CH CH C—OCH2COOH C—SMe CH H S-454 CH CHCH C—OCH2COOH C—SMe H S-455 CH CH CH CH C—OCH2COOH SMe S-456 C—SMe CH CHCH CH OCH2COOH S-457 CH C—SMe CH CH CH OCH2COOH S-458 CH CH C—SMe CH CHOCH2COOH S-459 CH CH C—SMe CH N OCH2COOH S-460 CH CH CH C—SMe CHOCH2COOH S-461 CH CH CH CH C—SMe OCH2COOH S-462 C—OCH2COOH C—SO2Me CH CHCH H S-463 CH C—OCH2COOH C—SO2Me CH CH H S-464 CH CH C—OCH2COOH C—SO2MeCH H S-465 CH CH CH C—OCH2COOH C—SO2Me H

TABLE 28 No. X1 X2 X3 X4 X5 R6 S-466 CH CH CH CH C—OCH2COOH SO2Me S-467C—SO2Me CH CH CH CH OCH2COOH S-468 CH C—SO2Me CH CH CH OCH2COOH S-469 CHCH C—SO2Me CH CH OCH2COOH S-470 CH CH C—SO2Me CH N OCH2COOH S-471 CH CHCH C—SO2Me CH OCH2COOH S-472 CH CH CH CH C—SO2Me OCH2COOH S-473C—OCH2COOH C—NHMe CH CH CH H S-474 CH C—OCH2COOH C—NHMe CH CH H S-475 CHCH C—OCH2COOH C—NHMe CH H S-476 CH CH CH C—OCH2COOH C—NHMe H S-477 CH CHCH CH C—OCH2COOH NHMe S-478 C—NHMe CH CH CH CH OCH2COOH S-479 CH C—NHMeCH CH CH OCH2COOH S-480 CH CH C—NHMe CH CH OCH2COOH S-481 CH CH CHC—NHMe CH OCH2COOH S-482 CH CH CH CH C—NHMe OCH2COOH S-483 C—OCH2COOHC—NHCOMe CH CH CH H S-484 CH C—OCH2COOH C—NHCOMe CH CH H S-485 CH CHC—OCH2COOH C—NHCOMe CH H S-486 CH CH CH C—OCH2COOH C—NHCOMe H S-487 CHCH CH CH C—OCH2COOH NHCOMe S-488 C—NHCOMe CH CH CH CH OCH2COOH S-489 CHC—NHCOMe CH CH CH OCH2COOH S-490 CH CH C—NHCOMe CH CH OCH2COOH S-491 CHCH C—NHCOMe CH N OCH2COOH S-492 CH CH CH C—NHCOMe CH OCH2COOH S-493 CHCH CH CH C—NHCOMe OCH2COOH S-494 C—OCH2COOH C—CN CH CH CH H S-495 CHC—OCH2COOH C—CN CH CH H S-496 CH CH C—OCH2COOH C—CN CH H

TABLE 29 No. X1 X2 X3 X4 X5 R6 S-497 CH CH CH C—OCH2COOH C—CN H S-498 CHCH CH CH C—OCH2COOH CN S-499 C—CN CH CH CH CH OCH2COOH S-500 CH C—CN CHCH CH OCH2COOH S-501 CH CH C—CN CH CH OCH2COOH S-502 CH CH C—CN CH NOCH2COOH S-503 CH CH CH C—CN CH OCH2COOH S-504 CH CH CH CH C—CN OCH2COOHS-505 C—OCH2COOH C—NO2 CH CH CH H S-506 CH C—OCH2COOH C—NO2 CH CH HS-507 CH CH C—OCH2COOH C—NO2 CH H S-508 CH CH CH C—OCH2COOH C—NO2 HS-509 CH CH CH CH C—OCH2COOH NO2 S-510 C—NO2 CH CH CH CH OCH2COOH S-511CH C—NO2 CH CH CH OCH2COOH S-512 CH CH C—NO2 CH CH OCH2COOH S-513 CH CHC—NO2 CH N OCH2COOH S-514 CH CH CH C—NO2 CH OCH2COOH S-515 CH CH CH CHC—NO2 OCH2COOH S-516 C—OCH2COOH C—Ph CH CH CH H S-517 CH C—OCH2COOH C—PhCH CH H S-518 CH CH C—OCH2COOH C—Ph CH H S-519 CH CH CH C—OCH2COOH C—PhH S-520 CH CH CH CH C—OCH2COOH Ph S-521 C—Ph CH CH CH CH OCH2COOH S-522CH C—Ph CH CH CH OCH2COOH S-523 CH CH C—Ph CH CH OCH2COOH S-524 CH CHC—Ph CH N OCH2COOH S-525 CH CH CH C—Ph CH OCH2COOH S-526 CH CH CH CHC—Ph OCH2COOH S-527 C—OCH2COOH C-2-pyridyl CH CH CH H

TABLE 30 No. X1 X2 X3 X4 X5 R6 S-528 CH C—OCH2COOH C-2-pyridyl CH CH HS-529 CH CH C—OCH2COOH C-2-pyridyl CH H S-530 CH CH CH C—OCH2COOHC-2-pyridyl H S-531 CH CH CH CH C—OCH2COOH 2-pyridyl S-532 C-2-pyridylCH CH CH CH OCH2COOH S-533 CH C-2-pyridyl CH CH CH OCH2COOH S-534 CH CHC-2-pyridyl CH CH OCH2COOH S-535 CH CH C-2-pyridyl CH N OCH2COOH S-536CH CH CH C-2-pyridyl CH OCH2COOH S-537 CH CH CH CH C-2-pyridyl OCH2COOHS-538 C—OCH2COOH C-2-furyl CH CH CH H S-539 CH C—OCH2COOH C-2-furyl CHCH H S-540 CH CH C—OCH2COOH C-2-furyl CH H S-541 CH CH CH C—OCH2COOHC-2-furyl H S-542 CH CH CH CH C—OCH2COOH 2-furyl S-543 C-2-furyl CH CHCH CH OCH2COOH S-544 CH C-2-furyl CH CH CH OCH2COOH S-545 CH CHC-2-furyl CH CH OCH2COOH S-546 CH CH C-2-furyl CH N OCH2COOH S-547 CH CHCH C-2-furyl CH OCH2COOH S-548 CH CH CH CH C-2-furyl OCH2COOH S-549C—OCH2COOH C-1,3-oxazol-2-yl CH CH CH H S-550 CH C—OCH2COOHC-1,3-oxazol-2-yl CH CH H S-551 CH CH C—OCH2COOH C-1,3-oxazol-2-yl CH HS-552 CH CH CH C—OCH2COOH C-1,3-oxazol-2-yl H S-553 CH CH CH CHC—OCH2COOH 1,3-oxazol-2-yl S-554 C-1,3-oxazol-2-yl CH CH CH CH OCH2COOHS-555 CH C-1,3-oxazol-2-yl CH CH CH OCH2COOH S-556 CH CHC-1,3-oxazol-2-yl CH CH OCH2COOH S-557 CH CH C-1,3-oxazol-2-yl CH NOCH2COOH S-558 CH CH CH C-1,3-oxazol-2-yl CH OCH2COOH

TABLE 31 No. X1 X2 X3 X4 X5 R6 S-559 CH CH CH CH C-1,3-oxazol-2-ylOCH2COOH S-560 C—OCH2COOH C-morpholino CH CH CH H S-561 CH C—OCH2COOHC-morpholino CH CH H S-562 CH CH C—OCH2COOH C-morpholino CH H S-563 CHCH CH C—OCH2COOH C-morpholino H S-564 CH CH CH CH C—OCH2COOH morpholinoS-565 C-morpholino CH CH CH CH OCH2COOH S-566 CH C-morpholino CH CH CHOCH2COOH S-567 CH CH C-morpholino CH CH OCH2COOH S-568 CH CHC-morpholino CH N OCH2COOH S-569 CH CH CH C-morpholino CH OCH2COOH S-570CH CH CH CH C-morpholino OCH2COOH S-571 C—OCH2COOH C—CONHMe CH CH CH HS-572 CH C—OCH2COOH C—CONHMe CH CH H S-573 CH CH C—OCH2COOH C—CONHMe CHH S-574 CH CH CH C—OCH2COOH C—CONHMe H S-575 CH CH CH CH C—OCH2COOHCONHMe S-576 C—CONHMe CH CH CH CH OCH2COOH S-577 CH C—CONHMe CH CH CHOCH2COOH S-578 CH CH C—CONHMe CH CH OCH2COOH S-579 CH CH C—CONHMe CH NOCH2COOH S-580 CH CH CH C—CONHMe CH OCH2COOH S-581 CH CH CH CH C—CONHMeOCH2COOH

TABLE 32 No. R⁷ R^(8a) Z R^(8b) R^(8c) U-1 OMe H C—H H H U-2 OMe H C—H HF U-3 OMe H C—H H Cl U-4 OMe H C—H H Me U-5 OMe H C—H F H U-6 OMe H C—HF F U-7 OMe H C—H F Cl U-8 OMe H C—H F Me U-9 OMe H C—H Cl H U-10 OMe HC—H Cl F U-11 OMe H C—H Cl Cl U-12 OMe H C—H Cl Me U-13 OMe H C—H Me HU-14 OMe H C—H Me F U-15 OMe H C—H Me Cl U-16 OMe H C—H Me Me U-17 OMe HC—F H Me U-18 OMe H C—F Me H U-19 OMe H C—Me H F U-20 OMe F C—H H MeU-21 OMe H N H H U-22 OMe H N H F U-23 OMe H N H Cl U-24 OMe H N H MeU-25 OMe H N F H U-26 OMe H N Cl H U-27 OMe H N Me H U-28 OMe F N H HU-29 OMe Cl N H H U-30 OMe Me N H H U-31 OEt H C—H H H U-32 OEt H C—H HF U-33 OEt H C—H H Cl U-34 OEt H C—H H Me U-35 OEt H C—H F H U-36 OEt HC—H F Cl U-37 OEt H C—H Cl F U-38 OEt H C—H Cl Cl U-39 OEt H C—H Me HU-40 OEt H C—F H Cl

TABLE 33 No. R⁷ R^(8a) Z R^(8b) R^(8c) U-41 OEt H C—F Cl H U-42 OEt HC—Cl H F U-43 OEt H C—Cl H Cl U-44 OEt H C—Cl Cl H U-45 OEt F C—H H ClU-46 OEt Cl C—H H Cl U-47 OEt H N H H U-48 OEt H N H F U-49 OEt H N H ClU-50 OEt H N H Me U-51 OEt H N F H U-52 OEt H N Cl H U-53 OEt H N Me HU-54 OEt F N H H U-55 OEt Cl N H H U-56 OEt Me N H H U-57 OCHMe₂ H C—H HH U-58 OCHMe₂ H C—H H F U-59 OCHMe₂ H C—H H Cl U-60 OCHMe₂ H C—H H MeU-61 OCHMe₂ H C—H F H U-62 OCHMe₂ H C—H F F U-63 OCHMe₂ H C—H F Cl U-64OCHMe₂ H C—H F Me U-65 OCHMe₂ H C—H Cl H U-66 OCHMe₂ H C—H Cl F U-67OCHMe₂ H C—H Cl Cl U-68 OCHMe₂ H C—H Cl Me U-69 OCHMe₂ H C—H Me H U-70OCHMe₂ H C—H Me F U-71 OCHMe₂ H C—H Me Cl U-72 OCHMe₂ H C—H Me Me U-73OCHMe₂ H C—F H F U-74 OCHMe₂ H C—F H Cl U-75 OCHMe₂ H C—F H Me U-76OCHMe₂ H C—F F H U-77 OCHMe₂ H C—F Cl H U-78 OCHMe₂ H C—F Me H U-79OCHMe₂ H C—Cl H F U-80 OCHMe₂ H C—Cl H Cl

TABLE 34 No. R⁷ R^(8a) Z R^(8b) R^(8c) U-81 OCHMe₂ H C—Cl H Me U-82OCHMe₂ H C—Cl Cl H U-83 OCHMe₂ H C—Cl Me H U-84 OCHMe₂ H C—Me H F U-85OCHMe₂ H C—Me H Cl U-86 OCHMe₂ H C—Me H Me U-87 OCHMe₂ H C—Me Me H U-88OCHMe₂ F C—H H F U-89 OCHMe₂ F C—H H Cl U-90 OCHMe₂ F C—H H Me U-91OCHMe₂ Cl C—H H Cl U-92 OCHMe₂ Cl C—H H Me U-93 OCHMe₂ Me C—H H Me U-94OCHMe₂ H N H H U-95 OCHMe₂ H N H F U-96 OCHMe₂ H N H Cl U-97 OCHMe₂ H NH Me U-98 OCHMe₂ H N F H U-99 OCHMe₂ H N Cl H U-100 OCHMe₂ H N Me HU-101 OCHMe₂ F N H H U-102 OCHMe₂ Cl N H H U-103 OCHMe₂ Me N H H U-104OCHMe(Et) H C—H H H U-105 OCHMe(Et) H C—H H F U-106 OCHMe(Et) H C—H H ClU-107 OCHMe(Et) H C—H H Me U-108 OCHMe(Et) H C—H F H U-109 OCHMe(Et) HC—H F F U-110 OCHMe(Et) H C—H F Cl U-111 OCHMe(Et) H C—H F Me U-112OCHMe(Et) H C—H Cl H U-113 OCHMe(Et) H C—H Cl F U-114 OCHMe(Et) H C—H ClCl U-115 OCHMe(Et) H C—H Cl Me U-116 OCHMe(Et) H C—H Me H U-117OCHMe(Et) H C—H Me F U-118 OCHMe(Et) H C—H Me Cl U-119 OCHMe(Et) H C—HMe Me U-120 OCHMe(Et) H C—F H F

TABLE 35 No. R⁷ R^(8a) Z R^(8b) R^(8c) U-121 OCHMe(Et) H C—F H Cl U-122OCHMe(Et) H C—F H Me U-123 OCHMe(Et) H C—F F H U-124 OCHMe(Et) H C—F ClH U-125 OCHMe(Et) H C—F Me H U-126 OCHMe(Et) H C—Cl H F U-127 OCHMe(Et)H C—Cl H Cl U-128 OCHMe(Et) H C—Cl H Me U-129 OCHMe(Et) H C—Cl Cl HU-130 OCHMe(Et) H C—Cl Me H U-131 OCHMe(Et) H C—Me H F U-132 OCHMe(Et) HC—Me H Cl U-133 OCHMe(Et) H C—Me H Me U-134 OCHMe(Et) H C—Me Me H U-135OCHMe(Et) F C—H H F U-136 OCHMe(Et) F C—H H Cl U-137 OCHMe(Et) F C—H HMe U-138 OCHMe(Et) Cl C—H H Cl U-139 OCHMe(Et) Cl C—H H Me U-140OCHMe(Et) Me C—H H Me U-141 OCHMe(Et) H N H H U-142 OCHMe(Et) H N H FU-143 OCHMe(Et) H N H Cl U-144 OCHMe(Et) H N H Me U-145 OCHMe(Et) H N FH U-146 OCHMe(Et) H N Cl H U-147 OCHMe(Et) H N Me H U-148 OCHMe(Et) F NH H U-149 OCHMe(Et) Cl N H H U-150 OCHMe(Et) Me N H H U-151 OCHF₂ H C—HH H U-152 OCHF₂ H C—H H F U-153 OCHF₂ H C—H H Cl U-154 OCHF₂ H C—H H MeU-155 OCHF₂ H C—H F H U-156 OCHF₂ H C—H Cl H U-157 OCHF₂ H C—H Me HU-158 OCHF₂ H N H H U-159 OCHF₂ H N H F U-160 OCHF₂ H N H Cl

TABLE 36 No. R⁷ R^(8a) Z R^(8b) R^(8c) U-161 OCHF₂ H N H Me U-162 OCHF₂H N F H U-163 OCHF₂ H N Cl H U-164 OCHF₂ H N Me H U-165 OCHF₂ F N H HU-166 OCHF₂ Cl N H H U-167 OCHF₂ Me N H H U-168 OCH₂Ph H C—H H H U-169OCH₂Ph H C—H H F U-170 OCH₂Ph H C—H H Cl U-171 OCH₂Ph H C—H H Me U-172OCH₂Ph H C—H F H U-173 OCH₂Ph H C—H Cl H U-174 OCH₂Ph H C—H Me H U-175OCH₂Ph H N H H U-176 OCH₂Ph H N H F U-177 OCH₂Ph H N H Cl U-178 OCH₂Ph HN H Me U-179 OCH₂Ph H N F H U-180 OCH₂Ph H N Cl H U-181 OCH₂Ph H N Me HU-182 OCH₂Ph F N H H U-183 OCH₂Ph Cl N H H U-184 OCH₂Ph Me N H H U-185OCHMe(Ph) H C—H H H U-186 OCHMe(Ph) H C—H H F U-187 OCHMe(Ph) H C—H H ClU-188 OCHMe(Ph) H C—H H Me U-189 OCHMe(Ph) H C—H F H U-190 OCHMe(Ph) HC—H Cl H U-191 OCHMe(Ph) H C—H Me H U-192 OCHMe(Ph) H C—H Me F U-193OCHMe(Ph) H C—H Me Cl U-194 OCHMe(Ph) H N H H U-195 OCHMe(Ph) H N H FU-196 OCHMe(Ph) H N H Cl U-197 OCHMe(Ph) H N H Me U-198 OCHMe(Ph) H N FH U-199 OCHMe(Ph) H N Cl H U-200 OCHMe(Ph) H N Me H

TABLE 37 No. R⁷ R^(8a) Z R^(8b) R^(8c) U-201 OCHMe(Ph) F N H H U-202OCHMe(Ph) Cl N H H U-203 OCHMe(Ph) Me N H H U-204 OPh H C—H H H U-205OPh H C—H H F U-206 OPh H C—H H Cl U-207 OPh H C—H H Me U-208 OPh H C—HF H U-209 OPh H C—H Cl H U-210 OPh H C—H Me H U-211 OPh H N H H U-212OPh H N H F U-213 OPh H N H Cl U-214 OPh H N H Me U-215 OPh H N F HU-216 OPh H N Cl H U-217 OPh H N Me H U-218 OPh F N H H U-219 OPh Cl N HH U-220 OPh Me N H H U-221 SMe H C—H H H U-222 SMe H C—H H F U-223 SMe HC—H H Cl U-224 SMe H C—H H Me U-225 SMe H C—H F H U-226 SMe H C—H Cl HU-227 SMe H C—H Me H U-228 SMe H N H H U-229 SMe H N H F U-230 SMe H N HCl U-231 SMe H N H Me U-232 SMe H N F H U-233 SMe H N Cl H U-234 SMe H NMe H U-235 SMe F N H H U-236 SMe Cl N H H U-237 SMe Me N H H U-238 SEt HC—H H H U-239 SEt H C—H H F U-240 SEt H C—H H Cl

TABLE 38 No. R⁷ R^(8a) Z R^(8b) R^(8c) U-241 SEt H C—H H Me U-242 SEt HC—H F H U-243 SEt H C—H Cl H U-244 SEt H C—H Me H U-245 SEt H N H HU-246 SEt H N H F U-247 SEt H N H Cl U-248 SEt H N H Me U-249 SEt H N FH U-250 SEt H N Cl H U-251 SEt H N Me H U-252 SEt F N H H U-253 SEt Cl NH H U-254 SEt Me N H H U-255 SCHMe₂ H C—H H H U-256 SCHMe₂ H C—H H FU-257 SCHMe₂ H C—H H Cl U-258 SCHMe₂ H C—H H Me U-259 SCHMe₂ H C—H F HU-260 SCHMe₂ H C—H F F U-261 SCHMe₂ H C—H F Cl U-262 SCHMe₂ H C—H F MeU-263 SCHMe₂ H C—H Cl H U-264 SCHMe₂ H C—H Cl F U-265 SCHMe₂ H C—H Cl ClU-266 SCHMe₂ H C—H Cl Me U-267 SCHMe₂ H C—H Me H U-268 SCHMe₂ H C—H Me FU-269 SCHMe₂ H C—H Me Cl U-270 SCHMe₂ H C—H Me Me U-271 SCHMe₂ H C—F H FU-272 SCHMe₂ H C—F H Cl U-273 SCHMe₂ H C—F H Me U-274 SCHMe₂ H C—F F HU-275 SCHMe₂ H C—F Cl H U-276 SCHMe₂ H C—F Me H U-277 SCHMe₂ H C—Cl H FU-278 SCHMe₂ H C—Cl H Cl U-279 SCHMe₂ H C—Cl H Me U-280 SCHMe₂ H C—Cl ClH

TABLE 39 No. R⁷ R^(8a) Z R^(8b) R^(8c) U-281 SCHMe₂ H C—Cl Me H U-282SCHMe₂ H C—Me H F U-283 SCHMe₂ H C—Me H Cl U-284 SCHMe₂ H C—Me H MeU-285 SCHMe₂ H C—Me Me H U-286 SCHMe₂ F C—H H F U-287 SCHMe₂ F C—H H ClU-288 SCHMe₂ F C—H H Me U-289 SCHMe₂ Cl C—H H Cl U-290 SCHMe₂ Cl C—H HMe U-291 SCHMe₂ Me C—H H Me U-292 SCHMe₂ H N H H U-293 SCHMe₂ H N H FU-294 SCHMe₂ H N H Cl U-295 SCHMe₂ H N H Me U-296 SCHMe₂ H N F H U-297SCHMe₂ H N Cl H U-298 SCHMe₂ H N Me H U-299 SCHMe₂ F N H H U-300 SCHMe₂Cl N H H U-301 SCHMe₂ Me N H H U-302 SCHMe(Et) H C—H H H U-303 SCHMe(Et)H C—H H F U-304 SCHMe(Et) H C—H H Cl U-305 SCHMe(Et) H C—H H Me U-306SCHMe(Et) H C—H F H U-307 SCHMe(Et) H C—H Cl H U-308 SCHMe(Et) H C—H MeH U-309 SCHMe(Et) H N H H U-310 SCHMe(Et) H N H F U-311 SCHMe(Et) H N HCl U-312 SCHMe(Et) H N H Me U-313 SCHMe(Et) H N F H U-314 SCHMe(Et) H NCl H U-315 SCHMe(Et) H N Me H U-316 SCHMe(Et) F N H H U-317 SCHMe(Et) ClN H H U-318 SCHMe(Et) Me N H H U-319 SCHF₂ H C—H H H U-320 SCHF₂ H C—H HF

TABLE 40 No. R⁷ R^(8a) Z R^(8b) R^(8c) U-321 SCHF₂ H C—H H Cl U-322SCHF₂ H C—H H Me U-323 SCHF₂ H N H H U-324 SCH₂Ph H C—H H H U-325 SCH₂PhH C—H H F U-326 SCH₂Ph H C—H H Cl U-327 SCH₂Ph H C—H H Me U-328 SCH₂Ph HN H H U-329 SCHMe(Ph) H C—H H H U-330 SCHMe(Ph) H C—H H F U-331SCHMe(Ph) H C—H H Cl U-332 SCHMe(Ph) H C—H H Me U-333 SCHMe(Ph) H N H HU-334 SPh H C—H H H U-335 SPh H C—H H F U-336 SPh H C—H H Cl U-337 SPh HC—H H Me U-338 SPh H N H H

A compound of the formula (IA) is shown below. (No. of Compound, part A,part B), (IA-1,S-1,U-57), (IA-2,S-2,U-57), (IA-3,S-3,U-57),(IA-4,S-4,U-57), (IA-5,S-5,U-57), (IA-7,S-7,U-57), (IA-8,S-8,U-57),(IA-9,S-9, U-57), (IA-10,S-10,U-57), (IA-11,S-11,U-57),(IA-12,S-12,U-57), (IA-13,S-13, U-57), (IA-14,S-14, U-57),(IA-15,S-15,U-57), (IA-16,S-16,U-57), (IA-17,S-17, U-57),(IA-18,S-18,U-57), (IA-19,S-19,U-57), (IA-20,S-20,U-57), (IA-21,S-21,U-57), (IA-22,S-22,U-57), (IA-23,S-23,U-57), (IA-24,S-24,U-57),(IA-25,S-25, U-57), (IA-26,S-26,U-57), (IA-27,S-27,U-57),(IA-28,S-28,U-57), (IA-29,S-29, U-57), (IA-30,S-30,U-57),(IA-31,S-31,U-57), (IA-32,S-32,U-57), (IA-33,S-33, U-57),(IA-34,S-34,U-57), (IA-35,S-35,U-57), (IA-36,S-36,U-57), (IA-37,S-37,U-57), (IA-38,S-38,U-57), (IA-39,S-39,U-57), (IA-40,S-40,U-57),(IA-41,S-41, U-57), (IA-42,S-42,U-57), (IA-43,S-43,U-57),(IA-44,S-44,U-57), (IA-45,S-45, U-57), (IA-46,S-46,U-57),(IA-47,S-47,U-57), (IA-48,S-48,U-57), (IA-49,S-49, U-57),(IA-50,S-50,U-57), (IA-51,S-51,U-57), (IA-52,S-52,U-57), (IA-53,S-53,U-57), (IA-54,S-54,U-57), (IA-55,S-55,U-57), (IA-56,S-56,U-57),(IA-57,S-57, U-57), (IA-58,S-58,U-57), (IA-59,S-59,U-57),(IA-60,S-60,U-57), (IA-61,S-61, U-57), (IA-62,S-62,U-57),(IA-63,S-63,U-57), (IA-64,S-64,U-57), (IA-65,S-65, U-57),(IA-66,S-66,U-57), (IA-67,S-67,U-57), (IA-68,S-68,U-57), (IA-69,S-69,U-57), (IA-70,S-70,U-57), (IA-71,S-71,U-57), (IA-72,S-72,U-57),(IA-73,S-73, U-57), (IA-74,S-74,U-57), (IA-75,S-75,U-57),(IA-76,S-76,U-57), (IA-77,S-77, U-57), (IA-78,S-78,U-57),(IA-79,S-79,U-57), (IA-80,S-80,U-57), (IA-81,S-81, U-57),(IA-82,S-82,U-57), (IA-83,S-83,U-57), (IA-84,S-84,U-57), (IA-85,S-85,U-57), (IA-86,S-86,U-57), (IA-87,S-87,U-57), (IA-88,S-88,U-57),(IA-89,S-89, U-57), (IA-90,S-90,U-57), (IA-91,S-91,U-57),(IA-92,S-92,U-57), (IA-93,S-93, U-57), (IA-94,S-94,U-57),(IA-95,S-95,U-57), (IA-96,S-96,U-57), (IA-97,S-97, U-57),(IA-98,S-98,U-57), (IA-99,S-99,U-57), (IA-100,S-100,U-57),(IA-101,S-101,U-57), (IA-102,S-102,U-57), (IA-103,S-103,U-57),(IA-104,S-104,U-57), (IA-105,S-105,U-57), (IA-106,S-106,U-57),(IA-107,S-107,U-57), (IA-108,S-108,U-57), (IA-109,S-109,U-57),(IA-110,S-110,U-57), (IA-111,S-111,U-57), (IA-112,S-112,U-57),(IA-113,S-113,U-57), (IA-114,S-114,U-57), (IA-115,S-115,U-57),(IA-116,S-116,U-57), (IA-117,S-117,U-57), (IA-118,S-118,U-57),(IA-119,S-119,U-57), (IA-120,S-120,U-57), (IA-121,S-121,U-57),(IA-122,S-122, U-57), (IA-123,S-123,U-57), (IA-124,S-124,U-57),(IA-125,S-125,U-57), (IA-126,S-126,U-57), (IA-127,S-127,U-57),(IA-128,S-128,U-57), (IA-129,S-129,U-57), (IA-130,S-130,U-57),(IA-131,S-131,U-57), (IA-132,S-132,U-57), (IA-133,S-133,U-57),(IA-134,S-134,U-57), (IA-135,S-135,U-57), (IA-136,S-136,U-57),(IA-137,S-137,U-57), (IA-138,S-138,U-57), (IA-139,S-139,U-57), (IA-140,S-140,U-57), (IA-141,S-141, U-57), (IA-142,S-142,U-57),(IA-143,S-143,U-57), (IA-144,S-144,U-57), (IA-145,S-145,U-57),(IA-146,S-146,U-57), (IA-147,S-147,U-57), (IA-148,S-148,U-57),(IA-149,S-149,U-57), (IA-150,S-150,U-57), (IA-151,S-151,U-57),(IA-152,S-152,U-57), (IA-153,S-153,U-57), (IA-154,S-154,U-57),(IA-155,S-155,U-57), (IA-156,S-156,U-57), (IA-157,S-157,U-57),(IA-158,S-158,U-57), (IA-159,S-159,U-57), (IA-160,S-160,U-57),(IA-161,S-161,U-57), (IA-162,S-162,U-57), (IA-163,S-163,U-57),(IA-164,S-164,U-57), (IA-165,S-165,U-57), (IA-166,S-166,U-57),(IA-167,S-167,U-57), (IA-168,S-168, U-57), (IA-169,S-169,U-57),(IA-170,S-170,U-57), (IA-171,S-171,U-57), (IA-172,S-172,U-57),(IA-173,S-173,U-57), (IA-174,S-174,U-57), (IA-175,S-175,U-57),(IA-176,S-176,U-57), (IA-177,S-177,U-57), (IA-178,S-178,U-57),(IA-179,S-179,U-57), (IA-180,S-180,U-57), (IA-181,S-181,U-57),(IA-182,S-182,U-57), (IA-183,S-183,U-57), (IA-184,S-184,U-57),(IA-185,S-185,U-57), (IA-186, S-186,U-57), (IA-187,S-187,U-57),(IA-188,S-188,U-57), (IA-189,S-189,U-57), (IA-190,S-190,U-57),(IA-191,S-191,U-57), (IA-192,S-192,U-57), (IA-193,S-193,U-57),(IA-194,S-194,U-57), (IA-195,S-195,U-57), (IA-196,S-196,U-57),(IA-197,S-197,U-57), (IA-198,S-198,U-57), (IA-199,S-199,U-57),(IA-201,S-201,U-57), (IA-202,S-202,U-57), (IA-203,S-203,U-57),(IA-204,S-204,U-57), (IA-205,S-205,U-57), (IA-206,S-206, U-57),(IA-207,S-207,U-57), (IA-210,S-210,U-57), (IA-211,S-211,U-57),(IA-212,S-212,U-57), (IA-213,S-213,U-57), (IA-214,S-214,U-57),(IA-215,S-215,U-57), (IA-216,S-216,U-57), (IA-217,S-217, U-57),(IA-218,S-218,U-57), (IA-219,S-219,U-57), (IA-220,S-220,U-57),(IA-221,S-221,U-57), (IA-222,S-222,U-57), (IA-223,S-223,U-57),(IA-224,S-224,U-57), (IA-225,S-225,U-57), (IA-226,S-226,U-57),(IA-227,S-227,U-57), (IA-228,S-228,U-57), (IA-229,S-229,U-57),(IA-230,S-230,U-57), (IA-231,S-231,U-57), (IA-232,S-232,U-57),(IA-233,S-233,U-57), (IA-234,S-234,U-57), (IA-235, S-235,U-57),(IA-236,S-236,U-57), (IA-237,S-237,U-57), (IA-238,S-238,U-57),(IA-239,S-239,U-57), (IA-240,S-240,U-57), (IA-241,S-241,U-57),(IA-242,S-242,U-57), (IA-243,S-243,U-57), (IA-244,S-244,U-57),(IA-245,S-245,U-57), (IA-246,S-246,U-57), (IA-247,S-247,U-57),(IA-248,S-248,U-57), (IA-249,S-249,U-57), (IA-250,S-250,U-57),(IA-251,S-251,U-57), (IA-252,S-252,U-57), (IA-253,S-253,U-57),(IA-254,S-254,U-57), (IA-255,S-255,U-57), (IA-256,S-256,U-57),(IA-257,S-257,U-57), (IA-258,S-258,U-57), (IA-259,S-259,U-57),(IA-260,S-260,U-57), (IA-261,S-261,U-57), (IA-262,S-262,U-57),(IA-263,S-263, U-57), (IA-264,S-264,U-57), (IA-265,S-265,U-57),(IA-266,S-266,U-57), (IA-267,S-267,U-57), (IA-268,S-268,U-57),(IA-269,S-269,U-57), (IA-270,S-270,U-57), (IA-271,S-271,U-57),(IA-272,S-272,U-57), (IA-273,S-273,U-57), (IA-274,S-274,U-57),(IA-275,S-275,U-57), (IA-276,S-276,U-57), (IA-277,S-277,U-57),(IA-278,S-278,U-57), (IA-279,S-279,U-57), (IA-280,S-280,U-57), (IA-281,S-281,U-57), (IA-282,S-282,U-57), (IA-283,S-283,U-57),(IA-284,S-284,U-57), (IA-285,S-285,U-57), (IA-286,S-286,U-57),(IA-287,S-287,U-57), (IA-288,S-288,U-57), (IA-289,S-289,U-57),(IA-290,S-290,U-57), (IA-291,S-291,U-57), (IA-292,S-292,U-57),(IA-293,S-293,U-57), (IA-294,S-294,U-57), (IA-295,S-295,U-57),(IA-296,S-296,U-57), (IA-297,S-297,U-57), (IA-298,S-298,U-57),(IA-299,S-299,U-57), (IA-300,S-300,U-57), (IA-301,S-301,U-57),(IA-302,S-302,U-57), (IA-303,S-303,U-57), (IA-304,S-304,U-57),(IA-305,S-305,U-57), (IA-306,S-306,U-57), (IA-307,S-307,U-57),(IA-308,S-308,U-57), (IA-309,S-309, U-57), (IA-310,S-310,U-57),(IA-311,S-311,U-57), (IA-312,S-312,U-57), (IA-313,S-313,U-57),(IA-314,S-314,U-57), (IA-315,S-315,U-57), (IA-316,S-316,U-57),(IA-317,S-317,U-57), (IA-318,S-318,U-57), (IA-319,S-319,U-57),(IA-320,S-320,U-57), (IA-321,S-321,U-57), (IA-322,S-322,U-57),(IA-323,S-323,U-57), (IA-324,S-324,U-57), (IA-325,S-325,U-57),(IA-326,S-326,U-57), (IA-327, S-327,U-57), (IA-328,S-328,U-57),(IA-329,S-329,U-57), (IA-330,S-330,U-57), (IA-331,S-331,U-57),(IA-332,S-332,U-57), (IA-333,S-333,U-57), (IA-334,S-334,U-57),(IA-335,S-335,U-57), (IA-336,S-336,U-57), (IA-337,S-337,U-57),(IA-338,S-338,U-57), (IA-339,S-339,U-57), (IA-340,S-340,U-57),(IA-341,S-341,U-57), (IA-342,S-342,U-57), (IA-343,S-343,U-57),(IA-344,S-344,U-57), (IA-345,S-345,U-57), (IA-346,S-346,U-57),(IA-347,S-347,U-57), (IA-348,S-348,U-57), (IA-349,S-349,U-57),(IA-350,S-350,U-57), (IA-351,S-351,U-57), (IA-352,S-352,U-57),(IA-353,S-353,U-57), (IA-354,S-354,U-57), (IA-355,S-355, U-57),(IA-356,S-356,U-57), (IA-357,S-357,U-57), (IA-358,S-358,U-57),(IA-359,S-359,U-57), (IA-360,S-360,U-57), (IA-361,S-361,U-57),(IA-362,S-362,U-57), (IA-363,S-363,U-57), (IA-364,S-364,U-57),(IA-365,S-365,U-57), (IA-366,S-366,U-57), (IA-367,S-367,U-57),(IA-368,S-368,U-57), (IA-369,S-369,U-57), (IA-370,S-370,U-57),(IA-371,S-371,U-57), (IA-372,S-372,U-57), (IA-373, S-373,U-57),(IA-374,S-374,U-57), (IA-375,S-375,U-57), (IA-376,S-376,U-57),(IA-377,S-377,U-57), (IA-378,S-378,U-57), (IA-379,S-379,U-57),(IA-380,S-380,U-57), (IA-381,S-381,U-57), (IA-382,S-382,U-57),(IA-383,S-383,U-57), (IA-384,S-384,U-57), (IA-385,S-385,U-57),(IA-386,S-386,U-57), (IA-387,S-387,U-57), (IA-388,S-388,U-57),

(IA-390,S-390,U-57), (IA-391,S-391,U-57), (IA-392,S-392,U-57),(IA-393,S-393,U-57), (IA-394,S-394,U-57), (IA-395,S-395,U-57),(IA-396,S-396,U-57), (IA-397,S-397,U-57), (IA-398,S-398,U-57),(IA-399,S-399,U-57), (IA-400,S-400,U-57), (IA-401,S-401,U-57),(IA-402,S-402,U-57), (IA-403,S-403,U-57), (IA-404,S-404,U-57),(IA-405,S-405,U-57), (IA-406,S-406,U-57), (IA-407,S-407, U-57),(IA-408,S-408,U-57), (IA-409,S-409,U-57), (IA-410,S-410,U-57),(IA-411,S-411,U-57), (IA-412,S-412,U-57), (IA-413,S-413,U-57),(IA-414,S-414,U-57), (IA-415,S-415,U-57), (IA-416,S-416,U-57),(IA-417,S-417,U-57), (IA-418,S-418,U-57), (IA-419,S-419,U-57),(IA-420,S-420,U-57), (IA-421,S-421,U-57), (IA-422,S-422,U-57),(IA-423,S-423,U-57), (IA-424,S-424,U-57), (IA-425, S-425,U-57),(IA-426,S-426,U-57), (IA-427,S-427,U-57), (IA-428,S-428,U-57),(IA-429,S-429,U-57), (IA-430,S-430,U-57), (IA-431,S-431,U-57),(IA-432,S-432,U-57), (IA-433,S-433,U-57), (IA-434,S-434,U-57),(IA-435,S-435,U-57), (IA-436,S-436,U-57), (IA-437,S-437,U-57),(IA-438,S-438,U-57), (IA-439,S-439,U-57), (IA-440,S-440,U-57),(IA-441,S-441,U-57), (IA-442,S-442,U-57), (IA-443,S-443,U-57),(IA-444,S-444,U-57), (IA-445,S-445,U-57), (IA-446,S-446,U-57),(IA-447,S-447,U-57), (IA-448,S-448,U-57), (IA-449,S-449,U-57),(IA-450,S-450,U-57), (IA-451,S-451,U-57), (IA-452,S-452,U-57),(IA-453,S-453, U-57), (IA-454,S-454,U-57), (IA-455,S-455,U-57),(IA-456,S-456,U-57), (IA-457,S-457,U-57), (IA-458,S-458,U-57),(IA-459,S-459,U-57), (IA-460,S-460,U-57), (IA-461,S-461,U-57),(IA-462,S-462,U-57), (IA-463,S-463,U-57), (IA-464,S-464,U-57),(IA-465,S-465,U-57), (IA-466,S-466,U-57), (IA-467,S-467,U-57),(IA-468,S-468,U-57), (IA-469,S-469,U-57), (IA-470,S-470,U-57), (IA-471,S-471,U-57), (IA-472,S-472,U-57), (IA-473,S-473,U-57),(IA-474,S-474,U-57), (IA-475,S-475,U-57), (IA-476,S-476,U-57),(IA-477,S-477,U-57), (IA-478,S-478,U-57), (IA-479,S-479,U-57),(IA-480,S-480,U-57), (IA-481,S-481,U-57), (IA-482,S-482,U-57),(IA-483,S-483,U-57), (IA-484,S-484,U-57), (IA-485,S-485,U-57),(IA-486,S-486,U-57), (IA-487,S-487,U-57), (IA-488,S-488,U-57),(IA-489,S-489,U-57), (IA-490,S-490,U-57), (IA-491,S-491,U-57),(IA-492,S-492,U-57), (IA-493,S-493,U-57), (IA-494,S-494,U-57),(IA-495,S-495,U-57), (IA-496,S-496,U-57), (IA-497,S-497,U-57),(IA-498,S-498,U-57), (IA-499,S-499, U-57), (IA-500,S-500,U-57),(IA-501,S-501,U-57), (IA-502,S-502,U-57), (IA-503,S-503,U-57),(IA-504,S-504,U-57), (IA-505,S-505,U-57), (IA-506,S-506,U-57),(IA-507,S-507,U-57), (IA-508,S-508,U-57), (IA-509,S-509,U-57),(IA-510,S-510,U-57), (IA-511,S-511,U-57), (IA-512,S-512,U-57),(IA-513,S-513,U-57), (IA-514,S-514,U-57), (IA-515,S-515,U-57),(IA-516,S-516,U-57), (IA-517, S-517,U-57), (IA-518,S-518,U-57),(IA-519,S-519,U-57), (IA-520,S-520,U-57), (IA-521,S-521,U-57),(IA-522,S-522,U-57), (IA-523,S-523,U-57), (IA-524,S-524,U-57),(IA-525,S-525,U-57), (IA-526,S-526,U-57), (IA-527,S-527,U-57),(IA-528,S-528,U-57), (IA-529,S-529,U-57), (IA-530,S-530,U-57),(IA-531,S-531,U-57), (IA-532,S-532,U-57), 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(IA-2052,S-200,U-243), (IA-2053,S-200,U-244),(IA-2054,S-200,U-245), (IA-2055,S-200,U-246), (IA-2056,S-200, U-247),(IA-2057,S-200,U-248), (IA-2058,S-200,U-249), (IA-2059,S-200,U-250),(IA-2060,S-200,U-251), (IA-2061,S-200,U-252), (IA-2062,S-200,U-253),(IA-2063,S-200,U-254), (IA-2064,S-200,U-255), (IA-2065,S-200,U-256),(IA-2066,S-200,U-257), (IA-2067,S-200,U-258), (IA-2068,S-200,U-259),(IA-2069,S-200,U-260), (IA-2070,S-200,U-261), (IA-2071,S-200,U-262),(IA-2072,S-200,U-263), (IA-2073,S-200,U-264), (IA-2074,S-200,U-265),(IA-2075,S-200, U-266), (IA-2076,S-200,U-267), (IA-2077,S-200,U-268),(IA-2078,S-200,U-269), (IA-2079,S-200,U-270), (IA-2080,S-200,U-271),(IA-2081,S-200,U-272), (IA-2082,S-200,U-273), (IA-2083,S-200,U-274),(IA-2084,S-200,U-275), (IA-2085,S-200,U-276), (IA-2086,S-200,U-277),(IA-2087,S-200,U-278), (IA-2088,S-200,U-279), (IA-2089,S-200,U-280),(IA-2090,S-200,U-281), (IA-2091,S-200,U-282), (IA-2092,S-200,U-283),(IA-2093,S-200,U-284), (IA-2094,S-200, U-285), (IA-2095,S-200,U-286),(IA-2096,S-200,U-287), (IA-2097,S-200,U-288), (IA-2098,S-200,U-289),(IA-2099,S-200,U-290), (IA-2100,S-200,U-291), (IA-2101,S-200,U-292),(IA-2102,S-200,U-293), (IA-2103,S-200,U-294), (IA-2104,S-200,U-295),(IA-2105,S-200,U-296), (IA-2106,S-200,U-297), (IA-2107,S-200,U-298),(IA-2108,S-200,U-299), (IA-2109,S-200,U-300), (IA-2110,S-200,U-301),(IA-2111,S-200,U-302), (IA-2112,S-200,U-303), (IA-2113,S-200, U-304),(IA-2114,S-200,U-305), (IA-2115,S-200,U-306), (IA-2116,S-200,U-307),(IA-2117,S-200,U-308), (IA-2118,S-200,U-309), (IA-2119,S-200,U-310),(IA-2120,S-200,U-311), (IA-2121,S-200,U-312), (IA-2122,S-200,U-313),(IA-2123,S-200,U-314), (IA-2124,S-200,U-315), (IA-2125,S-200,U-316),(IA-2126,S-200,U-317), (IA-2127,S-200,U-318), (IA-2128,S-200,U-319),(IA-2129,S-200,U-320), (IA-2130,S-200,U-321), (IA-2131,S-200,U-322),(IA-2132,S-200, U-323), (IA-2133,S-200,U-324), (IA-2134,S-200,U-325),(IA-2135,S-200,U-326), (IA-2136,S-200,U-327), (IA-2137,S-200,U-328),(IA-2138,S-200,U-329), (IA-2139,S-200,U-330), (IA-2140,S-200,U-331),(IA-2141,S-200,U-332), (IA-2142,S-200,U-333), (IA-2143,S-200,U-334),(IA-2144,S-200,U-335), (IA-2145,S-200,U-336), (IA-2146,S-200,U-337),(IA-2147,S-200,U-338), (IA-2148,S-201,U-1), (IA-2149,S-201,U-2),(IA-2150,S-201,U-3), (IA-2151,S-201,U-4), (IA-2152,S-201,U-5),(IA-2153,S-201,U-6), (IA-2154,S-201,U-7), (IA-2155,S-201,U-8),(IA-2156,S-201,U-9), (IA-2157,S-201,U-10), (IA-2158,S-201,U-11),(IA-2159,S-201,U-12), (IA-2160,S-201,U-13), (IA-2161,S-201,U-14),(IA-2162, S-201,U-15), (IA-2163,S-201,U-16), (IA-2164,S-201,U-17),(IA-2165,S-201, U-18), (IA-2166,S-201,U-19), (IA-2167,S-201,U-20),(IA-2168,S-201,U-21), (IA-2169,S-201,U-22), (IA-2170,S-201,U-23),(IA-2171,S-201,U-24), (IA-2172, S-201,U-25), (IA-2173,S-201,U-26),(IA-2174,S-201,U-27), (IA-2175,S-201, U-28), (IA-2176,S-201,U-29),(IA-2177,S-201,U-30), (IA-2178,S-201,U-31), (IA-2179,S-201,U-32),(IA-2180,S-201,U-33), (IA-2181,S-201,U-34), (IA-2182, S-201,U-35),(IA-2183,S-201,U-36), (IA-2184,S-201,U-37), (IA-2185,S-201, U-38),(IA-2186,S-201,U-39), (IA-2187,S-201,U-40), (IA-2188,S-201,U-41),(IA-2189,S-201,U-42), (IA-2190,S-201,U-43), (IA-2191,S-201,U-44),(IA-2192, S-201,U-45), (IA-2193,S-201,U-46), (IA-2194,S-201, U-47),(IA-2195,S-201, U-48), (IA-2196,S-201,U-49), (IA-2197,S-201,U-50),(IA-2198,S-201,U-51), (IA-2199,S-201,U-52), (IA-2200,S-201,U-53),(IA-2201,S-201,U-54), (IA-2202, S-201,U-55), (IA-2203,S-201,U-56),(IA-2204,S-201,U-62), (IA-2205,S-201, U-63), (IA-2206,S-201,U-64),(IA-2207,S-201,U-66), (IA-2208,S-201,U-67), (IA-2209,S-201,U-68),(IA-2210,S-201,U-70), (IA-2211,S-201,U-71), (IA-2212, S-201,U-72),(IA-2213,S-201,U-73), (IA-2214,S-201,U-75), (IA-2215,S-201, U-76),(IA-2216,S-201,U-77), (IA-2217,S-201,U-78), (IA-2218,S-201,U-79),(IA-2219,S-201,U-80), (IA-2220,S-201,U-81), (IA-2221,S-201,U-82),(IA-2222, S-201,U-83), (IA-2223,S-201,U-84), (IA-2224,S-201,U-85),(IA-2225,S-201, U-86), (IA-2226,S-201,U-87), (IA-2227,S-201,U-88),(IA-2228,S-201,U-89), (IA-2229,S-201,U-90), (IA-2230,S-201,U-91),(IA-2231,S-201,U-92), (IA-2232, S-201,U-93), (IA-2233,S-201,U-94),(IA-2234,S-201,U-95), (IA-2235,S-201, U-96), (IA-2236,S-201,U-97),(IA-2237,S-201,U-98), (IA-2238,S-201,U-99), (IA-2239,S-201,U-100),(IA-2240,S-201,U-101), (IA-2241,S-201,U-102), (IA-2242,S-201,U-103),(IA-2243,S-201,U-104), (IA-2244,S-201,U-105), (IA-2245, S-201,U-106),(IA-2246,S-201,U-107), (IA-2247,S-201,U-108), (IA-2248,S-201,U-109),(IA-2249,S-201,U-110), (IA-2250,S-201,U-111), (IA-2251,S-201, U-112),(IA-2252,S-201,U-113), (IA-2253,S-201,U-114), (IA-2254,S-201,U-115),(IA-2255,S-201,U-116), (IA-2256,S-201,U-117), (IA-2257,S-201,U-118),(IA-2258,S-201,U-119), (IA-2259,S-201,U-120), (IA-2260,S-201,U-121),(IA-2261,S-201,U-122), (IA-2262,S-201,U-123), (IA-2263,S-201,U-124),(IA-2264,S-201,U-125), (IA-2265,S-201,U-126), (IA-2266,S-201, U-127),(IA-2267,S-201,U-128), (IA-2268,S-201,U-129), (IA-2269,S-201,U-130),(IA-2270,S-201, U-131), (IA-2271,S-201,U-132), (IA-2272,S-201,U-133),(IA-2273,S-201,U-134), (IA-2274,S-201,U-135), (IA-2275,S-201,U-136),(IA-2276,S-201,U-137), (IA-2277,S-201,U-138), (IA-2278,S-201,U-139),(IA-2279,S-201,U-140), (IA-2280,S-201,U-141), (IA-2281,S-201,U-142),(IA-2282,S-201,U-143), (IA-2283,S-201,U-144), (IA-2284,S-201,U-145),(IA-2285,S-201,U-146), (IA-2286,S-201,U-147), (IA-2287,S-201,U-148),(IA-2288,S-201,U-149), (IA-2289,S-201, U-150), (IA-2290,S-201,U-151),(IA-2291,S-201,U-152), (IA-2292,S-201,U-153), (IA-2293,S-201,U-154),(IA-2294,S-201,U-155), (IA-2295,S-201,U-156), (IA-2296,S-201,U-157),(IA-2297,S-201,U-158), (IA-2298,S-201,U-159), (IA-2299,S-201,U-160),(IA-2300,S-201,U-161), (IA-2301,S-201,U-162), (IA-2302,S-201,U-163),(IA-2303,S-201,U-164), (IA-2304,S-201,U-165), (IA-2305,S-201,U-166),(IA-2306,S-201,U-167), (IA-2307,S-201,U-168), (IA-2308,S-201, U-169),(IA-2309,S-201,U-170), (IA-2310,S-201,U-171), (IA-2311,S-201,U-172),(IA-2312,S-201,U-173), (IA-2313,S-201,U-174), (IA-2314,S-201,U-175),(IA-2315,S-201,U-176), (IA-2316,S-201,U-177), (IA-2317,S-201,U-178),(IA-2318,S-201,U-179), (IA-2319,S-201,U-180), (IA-2320,S-201,U-181),(IA-2321,S-201,U-182), (IA-2322,S-201,U-183), (IA-2323,S-201,U-184),(IA-2324,S-201,U-185), (IA-2325,S-201,U-186), (IA-2326,S-201,U-187),(IA-2327,S-201, U-188), (IA-2328,S-201,U-189), (IA-2329,S-201,U-190),(IA-2330,S-201,U-191), (IA-2331,S-201,U-192), (IA-2332,S-201,U-193),(IA-2333,S-201,U-194), (IA-2334,S-201,U-195), (IA-2335,S-201,U-196),(IA-2336,S-201,U-197), (IA-2337,S-201,U-198), (IA-2338,S-201,U-199),(IA-2339,S-201,U-200), (IA-2340,S-201,U-201), (IA-2341,S-201,U-202),(IA-2342,S-201,U-203), (IA-2343,S-201,U-204), (IA-2344,S-201,U-205),(IA-2345,S-201,U-206), (IA-2346,S-201, U-207), (IA-2347,S-201,U-208),(IA-2348,S-201,U-209), (IA-2349,S-201,U-210), (IA-2350,S-201,U-211),(IA-2351,S-201,U-212), (IA-2352,S-201,U-213), (IA-2353,S-201,U-214),(IA-2354,S-201,U-215), (IA-2355,S-201,U-216), (IA-2356,S-201,U-217),(IA-2357,S-201,U-218), (IA-2358,S-201,U-219), (IA-2359,S-201,U-220),(IA-2360,S-201,U-221), (IA-2361,S-201,U-222), (IA-2362,S-201,U-223),(IA-2363,S-201,U-224), (IA-2364,S-201,U-225), (IA-2365,S-201, U-226),(IA-2366,S-201,U-227), (IA-2367,S-201,U-228), (IA-2368,S-201,U-229),(IA-2369,S-201,U-230), (IA-2370,S-201,U-231), (IA-2371,S-201,U-232),(IA-2372,S-201,U-233), (IA-2373,S-201,U-234), (IA-2374,S-201,U-235),(IA-2375,S-201,U-236), (IA-2376,S-201,U-237), (IA-2377,S-201,U-238),(IA-2378,S-201,U-239), (IA-2379,S-201,U-240), (IA-2380,S-201,U-241),(IA-2381,S-201,U-242), (IA-2382,S-201,U-243), (IA-2383,S-201,U-244),(IA-2384,S-201, U-245), (IA-2385,S-201,U-246), (IA-2386,S-201,U-247),(IA-2387,S-201,U-248), (IA-2388,S-201,U-249), (IA-2389,S-201,U-250),(IA-2390,S-201,U-251), (IA-2391,S-201,U-252), (IA-2392,S-201,U-253),(IA-2393,S-201,U-254), (IA-2394,S-201,U-255), (IA-2395,S-201,U-256),(IA-2396,S-201,U-257), (IA-2397,S-201,U-258), (IA-2398,S-201,U-259),(IA-2399,S-201,U-260), (IA-2400,S-201,U-261), (IA-2401,S-201,U-262),(IA-2402,S-201,U-263), (IA-2403,S-201, U-264), (IA-2404,S-201,U-265),(IA-2405,S-201,U-266), (IA-2406,S-201,U-267), (IA-2407,S-201,U-268),(IA-2408,S-201,U-269), (IA-2409,S-201,U-270), (IA-2410,S-201,U-271),(IA-2411,S-201,U-272), (IA-2412,S-201,U-273), (IA-2413,S-201,U-274),(IA-2414,S-201,U-275), (IA-2415,S-201,U-276), (IA-2416,S-201,U-277),(IA-2417,S-201,U-278), (IA-2418,S-201,U-279), (IA-2419,S-201, U-283),(IA-2423,S-201,U-284), (IA-2424,S-201,U-285), (IA-2425,S-201,U-286),(IA-2426,S-201,U-287), (IA-2427,S-201,U-288), (IA-2428,S-201,U-289),(IA-2429,S-201,U-290), (IA-2430,S-201,U-291), (IA-2431,S-201,U-292),(IA-2432,S-201,U-293), (IA-2433,S-201,U-294), (IA-2434,S-201,U-295),(IA-2435,S-201,U-296), (IA-2436,S-201,U-297), (IA-2437,S-201,U-298),(IA-2438,S-201,U-299), (IA-2439,S-201,U-300), (IA-2440,S-201,U-301),(IA-2441,S-201, U-302), (IA-2442,S-201,U-303), (IA-2443,S-201,U-304),(IA-2444,S-201,U-305), (IA-2445,S-201,U-306), (IA-2446,S-201,U-307),(IA-2447,S-201,U-308), (IA-2448,S-201,U-309), (IA-2449,S-201,U-310),(IA-2450,S-201,U-311), (IA-2451,S-201,U-312), (IA-2452,S-201,U-313),(IA-2453,S-201,U-314), (IA-2454,S-201,U-315), (IA-2455,S-201,U-316),(IA-2456,S-201,U-317), (IA-2457,S-201,U-318), (IA-2458,S-201,U-319),(IA-2459,S-201,U-320), (IA-2460,S-201, U-321), (IA-2461,S-201,U-322),(IA-2462,S-201,U-323), (IA-2463,S-201,U-324), (IA-2464,S-201,U-325),(IA-2465,S-201,U-326), (IA-2466,S-201,U-327), (IA-2467,S-201,U-328),(IA-2468,S-201,U-329), (IA-2469,S-201,U-330), (IA-2470,S-201,U-331),(IA-2471,S-201,U-332), (IA-2472,S-201,U-333), (IA-2473,S-201,U-334),(IA-2474,S-201,U-335), (IA-2475,S-201,U-336), (IA-2476,S-201,U-337),(IA-2477,S-201,U-338)

-   -   wherein —X¹═X²—X³═X⁴— is —C(R¹)═C(R²)—C(R³)═C(R⁴)—,        —N═C(R²)—C(R³)═C(R⁴)—, —C(R¹)═N—C(R³)═C(R⁴)—,        —C(R¹)═C(R²)—N═C(R⁴)— and —C(R¹)═C(R²)—C(R³)═N—;    -   X⁵ is —N═ or —C(R⁵)═;    -   R¹, R², R³, R⁴, R⁵ and R⁶ are independently a hydrogen atom, a        fluorine atom, a chlorine atom, a bromine atom, methyl,        trifluoromethyl, methyloxy, difluoromethyloxy, N-methylamino,        methylcarbonylamino, cyano, nitro, phenyl, 2-pyridyl, 2-furyl,        1,3-oxazol-2-yl, morpholino, N-methylcarbamoyl, carboxy,        carboxymethyl, or carboxymethyloxy;    -   Z is ═N or ═C(R^(8D))—;    -   R⁷ is independently methyloxy, ethyloxy, propyloxy,        isopropyloxy, n-butyloxy, isopropyloxy, s-butyloxy,        difluoromethyloxy, benzyloxy, phenoxy, methylthio, ethylthio,        isopropylthio, s-butylthio, difluoromethylthio, benzylthio or        phenylthio; and    -   R^(8A), R^(8B), R^(8C) and R^(8D) are independently, a hydrogen        atom, a fluorine atom, a chlorine atom, a bromine atom or        methyl;

A compound of the formula (IB) is shown below.

(No. of Compound, part A, part B), (IB-1,S-1,U-57), (IB-2,S-2,U-57),(IB-3, S-3,U-57), (IB-4,S-4,U-57), (IB-5,S-5,U-57), (IB-6,S-6,U-57),(IB-7,S-7,U-57), (IB-8,S-8,U-57), (IB-9,S-9,U-57), (IB-10,S-10,U-57),(IB-11,S-11,U-57), (IB-12,S-12,U-57), (IB-13,S-13,U-57),(IB-14,S-14,U-57), (IB-15,S-15,U-57), (IB-16,S-16,U-57),(IB-17,S-17,U-57), (IB-18,S-18,U-57), (IB-19,S-19,U-57),(IB-20,S-20,U-57), (IB-21,S-21,U-57), (IB-22,S-22,U-57),(IB-23,S-23,U-57), (IB-24,S-24,U-57), (IB-25,S-25,U-57),(IB-26,S-26,U-57), (IB-27,S-27,U-57), (IB-28,S-28,U-57),(IB-29,S-29,U-57), (IB-30,S-30,U-57), (IB-31,S-31,U-57),(IB-32,S-32,U-57), (IB-33,S-33,U-57), (IB-34,S-34,U-57),(IB-35,S-35,U-57), (IB-36,S-36,U-57), (IB-37,S-37,U-57),(IB-38,S-38,U-57), (IB-39,S-39,U-57), (IB-40,S-40,U-57),(IB-41,S-41,U-57), (IB-42,S-42,U-57), (IB-43,S-43,U-57),(IB-44,S-44,U-57), (IB-45,S-45,U-57), (IB-46,S-46,U-57),(IB-47,S-47,U-57), (IB-48,S-48,U-57), (IB-49,S-49, U-57),(IB-50,S-50,U-57), (IB-51,S-51, U-57), (IB-52,S-52,U-57),(IB-53,S-53,U-57), (IB-54,S-54,U-57), (IB-55,S-55,U-57),(IB-56,S-56,U-57), (IB-57,S-57,U-57), (IB-58,S-58,U-57),(IB-59,S-59,U-57), (IB-60,S-60,U-57), (IB-61,S-61,U-57),(IB-62,S-62,U-57), (IB-63,S-63,U-57), (IB-64,S-64,U-57),(IB-65,S-65,U-57), (IB-66,S-66,U-57), (IB-67,S-67,U-57),(IB-68,S-68,U-57), (IB-69,S-69,U-57), (IB-70,S-70,U-57),(IB-71,S-71,U-57), (IB-72,S-72,U-57), (IB-73,S-73,U-57),(IB-74,S-74,U-57), (IB-75,S-75,U-57), (IB-76,S-76,U-57),(IB-77,S-77,U-57), (IB-78,S-78,U-57), (IB-79,S-79,U-57),(IB-80,S-80,U-57), (IB-81,S-81,U-57), (IB-82,S-82,U-57),(IB-83,S-83,U-57), (IB-84,S-84,U-57), (IB-85,S-85,U-57),(IB-86,S-86,U-57), (IB-87,S-87,U-57), (IB-88,S-88,U-57),(IB-89,S-89,U-57), (IB-90,S-90,U-57), (IB-91,S-91,U-57), (IB-92, S-92,U-57), (IB-93,S-93,U-57), (IB-94,S-94,U-57), (IB-95,S-95,U-57),(IB-96,S-96,U-57), (IB-97,S-97,U-57), (IB-98,S-98,U-57),(IB-99,S-99,U-57), (IB-100,S-100,U-57), (IB-101,S-101, U-57),(IB-102,S-102,U-57), (IB-103,S-103,U-57), (IB-104,S-104,U-57),(IB-105,S-105,U-57), (IB-106,S-106,U-57), (IB-107,S-107,U-57),(IB-108,S-108,U-57), (IB-109,S-109,U-57), (IB-110,S-110,U-57),(IB-111,S-111,U-57), (IB-112,S-112,U-57), (IB-113,S-113,U-57), (IB-114,S-114,U-57), (IB-115,S-115,U-57), (IB-116,S-116,U-57),(IB-117,S-117,U-57), (IB-118,S-118,U-57), (IB-119,S-119,U-57),(IB-120,S-120,U-57), (IB-121, S-121,U-57), (IB-122,S-122,U-57),(IB-123,S-123,U-57), (IB-124,S-124,U-57), (IB-125,S-125,U-57),(IB-126,S-126,U-57), (IB-127,S-127,U-57), (IB-128,S-128,U-57),(IB-129,S-129,U-57), (IB-130,S-130,U-57), (IB-131,S-131,U-57),(IB-132,S-132,U-57), (IB-133,S-133,U-57), (IB-134,S-134,U-57),(IB-135,S-135,U-57), (IB-136,S-136,U-57), (IB-137,S-137,U-57),(IB-138,S-138,U-57), (IB-139,S-139,U-57), (IB-140,S-140,U-57),(IB-141,S-141,U-57), (IB-142,S-142, U-57), (IB-143,S-143,U-57),(IB-144,S-144,U-57), (IB-145,S-145,U-57), (IB-146,S-146,U-57),(IB-147,S-147,U-57), (IB-148,S-148,U-57), (IB-149,S-149, U-57),(IB-150,S-150,U-57), (IB-151,S-151,U-57), 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(IB-1879,S-200,U-68),(IB-1880,S-200,U-70), (IB-1881,S-200,U-71), (IB-1882,S-200, U-72),(IB-1883,S-200,U-73), (IB-1884,S-200,U-75), (IB-1885,S-200,U-76),(IB-1886,S-200,U-77), (IB-1887,S-200,U-78), (IB-1888,S-200,U-79),(IB-1889,S-200,U-80), (IB-1890,S-200,U-81), (IB-1891,S-200,U-82),(IB-1892,S-200,U-83), (IB-1893,S-200,U-84), (IB-1894,S-200,U-85),(IB-1895,S-200,U-86), (IB-1896,S-200,U-87), (IB-1897,S-200,U-88),(IB-1898,S-200,U-89), (IB-1899,S-200,U-90), (IB-1900,S-200,U-91),(IB-1901,S-200,U-92), (IB-1902,S-200,U-93), (IB-1903,S-200,U-94),(IB-1904,S-200,U-95), (IB-1905,S-200,U-96), (IB-1906,S-200,U-97),(IB-1907, S-200,U-98), (IB-1908,S-200,U-99), (IB-1909,S-200,U-100),(IB-1910,S-200, U-101), (IB-1911,S-200,U-102), (IB-1912,S-200,U-103),(IB-1913,S-200,U-104), (IB-1914,S-200,U-105), (IB-1915,S-200,U-106),(IB-1916,S-200,U-107), (IB-1917,S-200,U-108), (IB-1918,S-200,U-109),(IB-1919,S-200,U-110), (IB-1920,S-200,U-111), (IB-1921,S-200,U-112),(IB-1922,S-200,U-113), (IB-1923, S-200,U-114), (IB-1924,S-200,U-115),(IB-1925,S-200,U-116), (IB-1926,S-200,U-117), (IB-1927,S-200,U-118),(IB-1928,S-200,U-119), (IB-1929,S-200, U-120), (IB-1930,S-200,U-121),(IB-1931,S-200,U-122), (IB-1932,S-200,U-123), (IB-1933,S-200,U-124),(IB-1934,S-200,U-125), (IB-1935,S-200,U-126), (IB-1936,S-200,U-127),(IB-1937,S-200,U-128), (IB-1938,S-200,U-129), (IB-1939,S-200,U-130),(IB-1940,S-200,U-131), (IB-1941,S-200,U-132), (IB-1942, S-200,U-133),(IB-1943,S-200,U-134), (IB-1944,S-200,U-135), (IB-1945, S-200,U-136),(IB-1946,S-200,U-137), (IB-1947,S-200,U-138), (IB-1948,S-200,U-139),(IB-1949,S-200,U-140), (IB-1950,S-200,U-141), (IB-1951,S-200, U-142),(IB-1952,S-200,U-143), (IB-1953,S-200,U-144), (IB-1954,S-200,U-145),(IB-1955,S-200,U-146), (IB-1956,S-200,U-147), (IB-1957,S-200,U-148),(IB-1958,S-200,U-149), (IB-1959,S-200,U-150), (IB-1960,S-200,U-151),(IB-1961,S-200,U-152), (IB-1962,S-200,U-153), (IB-1963,S-200,U-154),(IB-1964, S-200,U-155), (IB-1965,S-200,U-156), (IB-1966,S-200,U-157),(IB-1967, S-200,U-158), (IB-1968,S-200,U-159), (IB-1969,S-200,U-160),(IB-1970,S-200,U-161), (IB-1971,S-200,U-162), (IB-1972,S-200,U-163),(IB-1973,S-200, U-164), (IB-1974,S-200,U-165), (IB-1975,S-200,U-166),(IB-1976,S-200,U-167), (IB-1977,S-200,U-168), (IB-1978,S-200,U-169),(IB-1979,S-200,U-170), (IB-1980,S-200,U-171), (IB-1981,S-200,U-172),(IB-1982,S-200,U-173), (IB-1983,S-200,U-174), (IB-1984,S-200,U-175),(IB-1985,S-200,U-176), (IB-1986, S-200,U-177), (IB-1987,S-200,U-178),(IB-1988,S-200,U-179), (IB-1989, S-200,U-180), (IB-1990,S-200,U-181),(IB-1991,S-200,U-182), (IB-1992,S-200,U-183), (IB-1993,S-200,U-184),(IB-1994,S-200, U-185), (IB-1995,S-200, U-186), (IB-1996,S-200,U-187),(IB-1997,S-200,U-188), (IB-1998,S-200,U-189), (IB-1999,S-200,U-190),(IB-2000,S-200,U-191), (IB-2001,S-200,U-192), (IB-2002,S-200,U-193),(IB-2003,S-200,U-194), (IB-2004,S-200,U-195), (IB-2005,S-200,U-196),(IB-2006,S-200,U-197), (IB-2007,S-200,U-198), (IB-2008, S-200,U-199),(IB-2009,S-200,U-200), (IB-2010,S-200,U-201), 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S-200,U-287), (IB-2097,S-200,U-288), (IB-2098,S-200,U-289),(IB-2099, S-200,U-290), (IB-2100,S-200,U-291), (IB-2101,S-200,U-292),(IB-2102,S-200,U-293), (IB-2103,S-200,U-294), (IB-2104,S-200,U-295),(IB-2105,S-200, U-296), (IB-2106,S-200,U-297), (IB-2107,S-200,U-298),(IB-2108,S-200,U-299), (IB-2109,S-200,U-300), (IB-2110,S-200,U-301),(IB-2111,S-200,U-302), (IB-2112,S-200,U-303), (IB-2113,S-200,U-304),(IB-2114,S-200,U-305), (IB-2115,S-200,U-306), (IB-2116,S-200,U-307),(IB-2117,S-200,U-308), (IB-2118, S-200,U-309), (IB-2119,S-200,U-310),(IB-2120,S-200,U-311), (IB-2121, S-200,U-312), (IB-2122,S-200,U-313),(IB-2123,S-200,U-314), (IB-2124,S-200,U-315), (IB-2125,S-200,U-316),(IB-2126,S-200,U-317), (IB-2127,S-200, U-318), (IB-2128,S-200,U-319),(IB-2129,S-200,U-320), (IB-2130,S-200,U-321), (IB-2131,S-200,U-322),(IB-2132,S-200,U-323), (IB-2133,S-200,U-324), (IB-2134,S-200,U-325),(IB-2135,S-200,U-326), (IB-2136,S-200,U-327), (IB-2137,S-200,U-328),(IB-2138,S-200,U-329), (IB-2139,S-200,U-330), (IB-2140, S-200,U-331),(IB-2141,S-200,U-332), (IB-2142,S-200,U-333), (IB-2143, S-200,U-334),(IB-2144,S-200,U-335), (IB-2145,S-200,U-336), (IB-2146,S-200,U-337),(IB-2147,S-200,U-338), (IB-2148,S-201,U-1), (IB-2149,S-201,U-2),(IB-2150,S-201,U-3), (IB-2151,S-201,U-4), (IB-2152,S-201,U-5), (IB-2153,S-201,U-6), (IB-2154,S-201,U-7), (IB-2155,S-201,U-8),(IB-2156,S-201,U-9), (IB-2157,S-201,U-10), (IB-2158,S-201,U-11),(IB-2159,S-201,U-12), (IB-2160, S-201,U-13), (IB-2161,S-201,U-14),(IB-2162,S-201,U-15), (IB-2163,S-201,U-16), (IB-2164,S-201,U-17),(IB-2165,S-201,U-18), (IB-2166,S-201,U-19), (IB-2167,S-201,U-20),(IB-2168,S-201,U-21), (IB-2169,S-201,U-22), (IB-2170,S-201,U-23),(IB-2171,S-201,U-24), (IB-2172,S-201,U-25), (IB-2173,S-201,U-26),(IB-2174,S-201,U-27), (IB-2175,S-201,U-28), (IB-2176,S-201,U-29),(IB-2177,S-201,U-30), (IB-2178,S-201,U-31), (IB-2179,S-201,U-32),(IB-2180,S-201,U-33), (IB-2181,S-201,U-34), (IB-2182,S-201,U-35),(IB-2183,S-201,U-36), (IB-2184,S-201,U-37), (IB-2185,S-201,U-38),(IB-2186,S-201,U-39), (IB-2187,S-201,U-40), (IB-2188,S-201,U-41),(IB-2189,S-201,U-42), (IB-2190,S-201,U-43), (IB-2191,S-201,U-44),(IB-2192,S-201,U-45), (IB-2193,S-201,U-46), (IB-2194,S-201,U-47),(IB-2195,S-201,U-48), (IB-2196,S-201,U-49), (IB-2197,S-201,U-50),(IB-2198,S-201,U-51), (IB-2199,S-201,U-52), (IB-2200,S-201,U-53),(IB-2201,S-201,U-54), (IB-2202,S-201,U-55), (IB-2203, S-201,U-56),(IB-2204,S-201,U-62), (IB-2205,S-201,U-63), (IB-2206,S-201,U-64),(IB-2207,S-201,U-66), (IB-2208,S-201,U-67), (IB-2209,S-201,U-68),(IB-2210,S-201,U-70), (IB-2211,S-201,U-71), (IB-2212,S-201,U-72),(IB-2213,S-201,U-73), (IB-2214,S-201,U-75), (IB-2215,S-201,U-76),(IB-2216,S-201,U-77), (IB-2217,S-201,U-78), (IB-2218,S-201,U-79),(IB-2219,S-201,U-80), (IB-2220,S-201,U-81), (IB-2221,S-201,U-82),(IB-2222,S-201,U-83), (IB-2223,S-201,U-84), (IB-2224,S-201,U-85),(IB-2225,S-201,U-86), (IB-2226,S-201,U-87), (IB-2227,S-201,U-88),(IB-2228,S-201,U-89), (IB-2229,S-201,U-90), (IB-2230,S-201,U-91),(IB-2231,S-201,U-92), (IB-2232,S-201,U-93), (IB-2233,S-201,U-94),(IB-2234,S-201,U-95), (IB-2235,S-201,U-96), (IB-2236,S-201, U-97),(IB-2237,S-201,U-98), (IB-2238,S-201,U-99), (IB-2239,S-201,U-100),(IB-2240,S-201,U-101), (IB-2241,S-201,U-102), (IB-2242,S-201,U-103),(IB-2243, S-201,U-104), (IB-2244,S-201,U-105), (IB-2245,S-201,U-106),(IB-2246, S-201,U-107), (IB-2247,S-201,U-108), (IB-2248,S-201,U-109),(IB-2249,S-201,U-110), (IB-2250,S-201,U-111), (IB-2251,S-201,U-112),(IB-2252,S-201, U-113), (IB-2253,S-201,U-114), (IB-2254,S-201,U-115),(IB-2255,S-201,U-116), (IB-2256,S-201,U-117), (IB-2257,S-201,U-118),(IB-2258,S-201,U-119), (IB-2259,S-201,U-120), (IB-2260,S-201,U-121),(IB-2261,S-201,U-122), (IB-2262,S-201,U-123), (IB-2263,S-201,U-124),(IB-2264,S-201,U-125), (IB-2265, S-201,U-126), (IB-2266,S-201,U-127),(IB-2267,S-201,U-128), (IB-2268, S-201,U-129), (IB-2269,S-201,U-130),(IB-2270,S-201,U-131), (IB-2271,S-201,U-132), (IB-2272,S-201,U-133),(IB-2273,S-201,U-134), (IB-2274,S-201, U-135), (IB-2275,S-201,U-136),(IB-2276,S-201,U-137), (IB-2277,S-201,U-138), (IB-2278,S-201,U-139),(IB-2279,S-201,U-140), (IB-2280,S-201,U-141), (IB-2281,S-201,U-142),(IB-2282,S-201,U-143), (IB-2283,S-201,U-144), (IB-2284,S-201,U-145),(IB-2285,S-201,U-146), (IB-2286,S-201,U-147), (IB-2287, S-201,U-148),(IB-2288,S-201,U-149), (IB-2289,S-201,U-150), (IB-2290, S-201,U-151),(IB-2291,S-201,U-152), (IB-2292,S-201,U-153), (IB-2293,S-201,U-154),(IB-2294,S-201,U-155), (IB-2295,S-201,U-156), (IB-2296,S-201, U-157),(IB-2297,S-201,U-158), (IB-2298,S-201,U-159), (IB-2299,S-201,U-160),(IB-2300,S-201,U-161), (IB-2301,S-201,U-162), (IB-2302,S-201,U-163),(IB-2303,S-201,U-164), (IB-2304,S-201,U-165), (IB-2305,S-201,U-166),(IB-2306,S-201,U-167), (IB-2307,S-201,U-168), (IB-2308,S-201,U-169),(IB-2309, S-201,U-170), (IB-2310,S-201,U-171), (IB-2311,S-201,U-172),(IB-2312, S-201,U-173), (IB-2313,S-201,U-174), (IB-2314,S-201,U-175),(IB-2315,S-201,U-176), (IB-2316,S-201,U-177), (IB-2317,S-201,U-178),(IB-2318,S-201, U-179), (IB-2319,S-201,U-180), (IB-2320,S-201,U-181),(IB-2321,S-201,U-182), (IB-2322,S-201,U-183), (IB-2323,S-201,U-184),(IB-2324,S-201,U-185), (IB-2325,S-201,U-186), (IB-2326,S-201,U-187),(IB-2327,S-201,U-188), (IB-2328,S-201,U-189), (IB-2329,S-201,U-190),(IB-2330,S-201,U-191), (IB-2331, S-201,U-192), (IB-2332,S-201,U-193),(IB-2333,S-201,U-194), (IB-2334, S-201,U-195), (IB-2335,S-201,U-196),(IB-2336,S-201,U-197), (IB-2337,S-201,U-198), (IB-2338,S-201,U-199),(IB-2339,S-201,U-200), (IB-2340,S-201, U-201), (IB-2341,S-201,U-202),(IB-2342,S-201,U-203), (IB-2343,S-201,U-204), (IB-2344,S-201,U-205),(IB-2345,S-201,U-206), (IB-2346,S-201,U-207), (IB-2347,S-201,U-208),(IB-2348,S-201,U-209), (IB-2349,S-201,U-210), (IB-2350,S-201,U-211),(IB-2351,S-201,U-212), (IB-2352,S-201,U-213), (IB-2353, S-201,U-214),(IB-2354,S-201,U-215), (IB-2355,S-201,U-216), (IB-2356, S-201,U-217),(IB-2357,S-201,U-218), (IB-2358,S-201,U-219), (IB-2359,S-201,U-220),(IB-2360,S-201,U-221), (IB-2361,S-201,U-222), (IB-2362,S-201, U-223),(IB-2363,S-201,U-224), (IB-2364,S-201,U-225), (IB-2365,S-201,U-226),(IB-2366,S-201,U-227), (IB-2367,S-201,U-228), (IB-2368,S-201,U-229),(IB-2369,S-201,U-230), (IB-2370,S-201,U-231), (IB-2371,S-201,U-232),(IB-2372, 8-201,U-233), (IB-2373,S-201,U-234), (IB-2374,S-201,U-235),(IB-2375, S-201,U-236), (IB-2376,S-201,U-237), (IB-2377,S-201,U-238),(IB-2378, S-201,U-239), (IB-2379,S-201,U-240), (IB-2380,S-201,U-241),(IB-2381,S-201,U-242), (IB-2382,S-201,U-243), (IB-2383,S-201,U-244),(IB-2384,S-201, U-245), (IB-2385,S-201,U-246), (IB-2386,S-201,U-247),(IB-2387,S-201,U-248), (IB-2388,S-201,U-249), (IB-2389,S-201,U-250),(IB-2390,S-201,U-251), (IB-2391,S-201,U-252), (IB-2392,S-201,U-253),(IB-2393,S-201,U-254), (IB-2394,S-201,U-255), (IB-2395,S-201,U-256),(IB-2396,S-201,U-257), (IB-2397, S-201,U-258), (IB-2398,S-201,U-259),(IB-2399,S-201,U-260), (IB-2400, S-201,U-261), (IB-2401,S-201,U-262),(IB-2402,S-201,U-263), (IB-2403,S-201,U-264), (IB-2404,S-201,U-265),(IB-2405,S-201,U-266), (IB-2406,S-201, U-267), (IB-2407,S-201,U-268),(IB-2408,S-201,U-269), (IB-2409,S-201,U-270), (IB-2410,S-201,U-271),(IB-2411,S-201,U-272), (IB-2412,S-201,U-273), (IB-2413,S-201,U-274),(IB-2414,S-201,U-275), (IB-2415,S-201,U-276), (IB-2416,S-201,U-277),(IB-2417,S-201,U-278), (IB-2418,S-201,U-279), (IB-2419, S-201,U-280),(IB-2420,S-201,U-281), (IB-2421,S-201,U-282), (IB-2422, S-201, U-283),(IB-2423, S-201,U-284), (IB-2424,S-201,U-285), (IB-2425,S-201,U-286),(IB-2426,S-201,U-287), (IB-2427,S-201,U-288), (IB-2428,S-201, U-289),(IB-2429,S-201,U-290), (IB-2430,S-201,U-291), (IB-2431,S-201,U-292),(IB-2432,S-201,U-293), (IB-2433,S-201,U-294), (IB-2434,S-201,U-295),(IB-2435,S-201,U-296), (IB-2436, S-201,U-297), (IB-2437,S-201,U-298),(IB-2438,S-201,U-299), (IB-2439,S-201,U-300), (IB-2440,S-201,U-301),(IB-2441, S-201,U-302), (IB-2442,S-201,U-303), (IB-2443,S-201,U-304),(IB-2444, S-201,U-305), (IB-2445,S-201,U-306), (IB-2446,S-201,U-307),(IB-2447,S-201,U-308), (IB-2448,S-201,U-309), (IB-2449,S-201,U-310),(IB-2450,S-201, U-311), (IB-2451,S-201,U-312), (IB-2452,S-201,U-313),(IB-2453,S-201,U-314), (IB-2454,S-201,U-315), (IB-2455,S-201,U-316),(IB-2456,S-201,U-317), (IB-2457,S-201,U-318), (IB-2458,S-201,U-319),(IB-2459,S-201,U-320), (IB-2460,S-201,U-321), (IB-2461,S-201,U-322),(IB-2462,S-201,U-323), (IB-2463, S-201,U-324), (IB-2464,S-201,U-325),(IB-2465,S-201,U-326), (IB-2466, S-201,U-327), (IB-2467,S-201,U-328),(IB-2468,S-201,U-329), (IB-2469,S-201,U-330), (IB-2470,S-201,U-331),(IB-2471,S-201,U-332), (IB-2472,S-201, U-333), (IB-2473, S-201,U-334),(IB-2474,S-201,U-335), (IB-2475,S-201,U-336), (IB-2476,S-201,U-337),(IB-2477,S-201,U-338)

Test Example 1 DP Inhibitory Activity In Vitro

1) Preparation of Platelet and a Method of cAMP Assay

30 mL of peripheral blood was collected from a healthy volunteer using asyringe containing one ninth amount of 3.8% sodium citrate. After beingcentrifuged at 180 g for 10 minutes at room temperature, a supernatantwas collected and used as Platelet Rich Plasma (PRP). The resulting PRPwas washed with wash buffer and centrifuged three times (WashedPlatelet: WP) and platelets were counted by a microcell counter. WP wasadded to a plate in amount of 1.5×10⁸/assay and the plate was treatedwith 3-isobutyl-1-methylxanthin (IBMX; 0.5 mM) for 5 minutes. A reactionwas initiated by adding 100 nM of PGD2 5 min after an addition of a testcompound. The reaction was terminated with an addition of 1Nhydrochloric acid after 2 minutes and the cells were destructed using12% triton X-100. An amount of cAMP in the supernatant was assayed byHomogeneous Trangient Fluorescence (HTRF)

2) Receptor Binding Assay

A prepared WP was homogenated and a membrane fraction was collected withhigh-speed centrifugation. A compound of the present invention was addedto the plate and [³H]-PGD2 was also added. A platelet membrane, aprotein concentration is 2 mg/mL, was added and mixed in the plate, andplaced on ice for 2 hours. The reaction solution was transferred to alow protein-adsorptive filter and washed with a wash solution eighttimes using a cell harvester. After the final washing, water was removedsufficiently, and scintillator was added. DP inhibitory activity wasinvestigated by measuring [³H] by using Micro Beta.

50% DP-inhibitory concentrations (IC50) in the cAMP assay and Ki valuesin the receptor binding assay were shown in Table 41.

3) Prostanoid Agonist and Antagonist Assay

Agonistic and antagonistic activities of the compounds of the presentinvention against prostanoid receptor were evaluated based onintracellular calcium flux or cAMP-production as an indicator using HEK293 cells expressing human EP1, EP2, EP3, EP4, FP, TP and IPrespectively. Any compounds did not show an agonistic activity againsteach prostanoid. In the other hand, more than twenty times potentantagonistic activity (IC50) was found in every compound compared withIC50 of cAMP assay with WP.

TABLE 41 Compd. IC50 Ki No. (nM) (nM) I-1 4.7 7.7 I-5 4.1 22 I-6 4.8 I-71.8 I-8 4.9 I-9 2.0 I-10 6.9 I-11 4.9 I-12 6.9 I-14 2.2 5.6 I-16 1.3I-20 3.8 I-21 3.0 I-23 1.6 1.4 I-30 1.2 5.4 I-31 2.9 4.3 I-32 7.0

Test Example 2 Test Using OVA Asthma Model of Rat

Brown Norway (BN) Rats were sensitized by i.p. administration of 0.1mg/mL of ovalbumin (OVA) and 1 mg of aluminum hydroxide gel. A solutionof 1% OVA was aerosolized by ultrasonic nebulizer (NE-U17) and the ratswere subjected to inhalation exposure of the aerosol for 30 minutes inan exposing chamber 12, 19, 26 and 33 days after the sensitization. Onehour before the 4th exposure of the antigen, compounds of the presentinvention were administered in a dose of 10 mg/kg p.o. once a day forthree days consecutively. In a control group, 0.5% of methyl cellulosewas administered in place of the compound of the present invention.

Under pentobarbital anesthesia (80 mg/kg, i.p.), acetylcholine (3.9,7.8, 15.6, 31.3, 62.5, 125, 250 and 500 μg/kg) was injected to jugularvein of the rats successively from a lower dose at intervals of 5minutes three days after the fourth exposure to the antigen, andimmediate contractile reaction of airways (an increase of insufflationpressure) was measured by a modified method of Konnzett & Rossler.Inhibition rate of increased hyperresponsive airway against the controlgroup was calculated based on area under the curve (AUC) obtained fromconcentration-response curve of acetylcholine.

After the measurement of increased hyperresponsive airway was completed,bronchoalveoli of the rats were washed with 5 mL of saline three times.Total cell number in the washings was counted by a hemacytometer underlight microscope, and inhibition rates of infiltration of inflammatorycells against the control group were calculated. Further, mucin in theairway lavage fluid was measured by ELISA method using jacalin, amucin-binding lectin, and the inhibition rates of mucus-secretionagainst the control group were calculated.

Results were shown in Table 42.

TABLE 42 inhibition rate (%) infiltration of Compd. dose airwayinflammatory mucus- No. (mg/kg) hyperresponsiveness cells secretion I-110 43 58 52 I-11 10 77 56 30 I-23 10 46 79 72

Test Example 3 Test Using Nasal Congestion Model of Guinea Pig

Methods of measuring nasal airway resistance and evaluating anti-nasalcongestion activity using a guinea pig were illustrated below.

A 1% solution of ovalbumin (OVA) was aerosolized by ultrasonicnebulizer, a male Hartley guinea pigs were sensitized by inhalation ofthe aerosol for 10 minutes twice at an interval of a week and a reactionwas initiated by exposure to the antigen 7 days later. Trachea of theguinea pig was incised under pentobarbital anesthesia (30 mg/kg, i.p.),and cannulae were fitted at the sides of nasal cavity and lungrespectively. To the lung side, a ventilator supplying 4 mL of air everytime at a rate of 60 times/min was connected. Spontaneous breathing ofthe guinea pig was stopped by the administration of gallamine (2 mg/kg,i.v.) and 4 mL of air every time was supplied at a rate of 70times/minute to rostrum of nose through the cannula of the nasal sideusing a ventilator. Air pressure necessary for supplying the air wasmeasured by a transducer fitted at the side branch and used as anindicator for resistance of nasal cavity. Exposure to the antigen wasperformed by generating the aerosol of 3% OVA solution between theventilator and the nasal cavity cannula for three minutes. Compounds ofthe present invention were administered intravenously 10 minutes beforethe exposure to the antigen. Resistance of nasal cavity was continuouslymeasured during a period from 0 to 30 minutes, and the inhibition rateagainst the vehicle was obtained based on AUC of the 30 minutes, whichwas recorded with resistance of nasal cavity (cm H₂O) as a longitudinalaxis, and time (from 0 to 30 min.) as an abscissa axis.

Formulation Example

The following formulating examples 1-8 are just for illustrativepurposes and not intended to limit the range of the present invention. Aterm of “active ingredient” means the compounds of the presentinvention, pharmaceutically acceptable salt or hydrate thereof.

Formulation Example 1

A hard-gelatin capsule is prepared with the following ingredients;

Amount (mg/capsule) active ingredient 250 starch (dried) 200 magnesiumstearate 10 Total 460 mg

Formulation Example 2

A tablet is prepared with the following ingredients;

Amount (mg/tablet) active ingredient 250 cellulose (micro crystalline)400 silicon dioxide (fume) 10 stearic acid 5 Total 665 mg

The ingredients above are mixed and compressed to give a tablet weighing665 mg/tablet.

Formulation Example 3

An aerosol solution is prepared with the following ingredients;

weight active ingredient  0.25 ethanol  25.75 propellant22(chlorodifluoroethane)  74.00 Total 100.00

The active ingredient and ethanol are mixed and the mixture is added toa part of propellant 22, and the resulting solution is transferred to afilling apparatus after being cooled to −30° C. Next, the necessaryamount is provided to a stainless-steel vessel and the content isdiluted with the remaining propellant. A valve unit is fitted to thevessel.

Formulation Example 4

A tablet containing 60 mg of an active ingredient is prepared asfollows;

active ingredient 60 mg starch 45 mg microcrystalline cellulose 35 mgpolyvinylpyrrolidone 4 mg (10% aq. solution) sodium carboxymethylstarch4.5 mg magnesium stearate 0.5 mg talc 1 mg Total 150 mg

The active ingredient, starch and cellulose are put through a sieve ofNo. 45 mesh US and mixed sufficiently. The resulting powder is mixedwith a solution containing polyvinylpyrrolidone and the mixture is putthrough a sieve of No. 14 mesh US. The granulated powder is dried at 50°C. and put through a sieve of No. 18 mesh US. Sodiumcarboxymethylstarch, magnesium stearate and talc are put through a sieveof No. 60 mesh US in advance and added to the granulated powder, mixedand compressed by a tableting machine to give a tablet weighing 150mg/tablet.

Formulation Example 5

A capsule containing 80 mg of an active ingredient is prepared asfollows;

active ingredient 80 mg starch 59 mg microcrystalline cellulose 59 mgmagnesium stearate 2 mg Total 200 mg

The active ingredient, starch, cellulose and magnesium stearate aremixed, put through a sieve of No. 45 mesh US and filled in hard-gelatincapsules to give a capsule formulation containing 200 mg/capsule.

Formulation Example 6

A suppository containing 225 mg of an active ingredient is prepared asfollows;

active ingredient 225 mg saturated fatty acid gliceride 2000 mg Total2225 mg

The active ingredient is put through a sieve of No. 60 mesh US andsuspended in the saturated fatty acid gliceride melted by the leastamount of heating. Then, the mixture was cooled in a mold of 2 g inappearance.

Formulation Example 7

A suspension containing 50 mg of an active ingredient is prepared asfollows;

active ingredient 50 mg sodium carboxymethylcellulose 50 mg syrup 1.25ml solution of benzoic acid 0.10 ml flavor q.v. pigment q.v. Total(adding purified water) 5 ml

The active ingredient is put through a sieve of No. 45 mesh US and mixedwith sodium carboxymethylcellulose and syrup to give a smooth paste. Thesolution of benzoic acid and flavor are diluted with a part of water andadded to the paste and stirred. A necessary amount of water is added togive the objective suspension.

Formulation Example 8

A formulation for i.v. injection is prepared as follows;

active ingredient 100 mg saturated fatty acid gliceride 1000 ml

The solution containing the active ingredient above is usually injectedintravenously to a patient at a rate of 1 ml/min.

INDUSTRIAL APPLICABILITY

It was found that a novel indole derivative had a DP receptorantagonistic activity and was effective on treating allergic diseases.

1-20. (canceled)
 21. A compound of the general formula (I):

wherein the ring A is an aromatic carbocyclic ring or an aromaticheterocyclic ring; the ring B is pyrrolidine; X¹ is —C(R¹)═; X² is—C(R²)═; X³ is —C(R³)═; X⁴ is —C(R⁴)═; X⁵ is —N═; R¹, R², R³, R⁴ and R⁶are independently a hydrogen atom, a halogen atom, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, hydroxy, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted cycloalkyloxy, optionally substitutedcycloalkenyloxy, mercapto, optionally substituted alkylthio, optionallysubstituted alkenylthio, optionally substituted alkynylthio, optionallysubstituted alkylsulfinyl, optionally substituted alkylsulfonyl,optionally substituted alkylsulfonyloxy, optionally substitutedcycloalkylthio, optionally substituted cycloalkylsulfinyl, optionallysubstituted cycloalkylsulfonyl, optionally substitutedcycloalkylsulfonyloxy, optionally substituted cycloalkenylthio,optionally substituted cycloalkenylsulfinyl, optionally substitutedcycloalkenylsulfonyl, optionally substituted cycloalkenylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted aryloxycarbonyl,optionally substituted carbamoyl, optionally substituted sulfamoyl,cyano, nitro, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted arylthio, optionally substitutedarylsulfinyl, optionally substituted arylsulfonyl, optionallysubstituted arylsulfonyloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroarylthio, optionally substituted heteroarylsulfinyl, optionallysubstituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, an optionally substituted non-aromaticheterocyclic group or a group of the formula: -L³-R¹⁰, wherein R¹⁰ ishydroxyalkyl, carboxy, alkyloxycarbonyl, optionally substitutedcarbamoyl or a carboxy equivalent, and L³ is a single bond, optionallysubstituted alkylene optionally containing one or two heteroatom(s),optionally substituted alkenylene optionally containing one or twoheteroatom(s), optionally substituted alkynylene optionally containingone or two heteroatom(s), an oxygen atom, a sulfur atom or —N(R¹¹)—,provided that at least one of R¹, R², R³, R⁴ and R⁶ is a group of-L³-R¹⁰; R⁷ is a hydrogen atom, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted cycloalkyloxy, optionally substitutedcycloalkenyloxy, optionally substituted aryloxy, optionally substitutedheteroaryloxy, optionally substituted alkylthio, optionally substitutedalkenylthio, optionally substituted alkynylthio, optionally substitutedcycloalkylthio, optionally substituted cycloalkenylthio, optionallysubstituted arylthio or optionally substituted heteroarylthio; R⁸ isindependently a halogen atom, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkenyl, hydroxy,optionally substituted alkyloxy, optionally substituted alkenyloxy,optionally substituted alkynyloxy, optionally substituted cycloalkyloxy,optionally substituted cycloalkenyloxy, mercapto, optionally substitutedalkylthio, optionally substituted alkenylthio, optionally substitutedalkynylthio, optionally substituted alkylsulfinyl, optionallysubstituted alkylsulfonyl, optionally substituted alkylsulfonyloxy,optionally substituted cycloalkylthio, optionally substitutedcycloalkylsulfinyl, optionally substituted cycloalkylsulfonyl,optionally substituted cycloalkylsulfonyloxy, optionally substitutedcycloalkenylthio, optionally substituted cycloalkenylsulfinyl,optionally substituted cycloalkenylsulfonyl, optionally substitutedcycloalkenylsulfonyloxy, optionally substituted amino, acyl, optionallysubstituted alkyloxycarbonyl, optionally substituted alkenyloxycarbonyl,optionally substituted alkynyloxycarbonyl, optionally substitutedaryloxycarbonyl, optionally substituted carbamoyl, optionallysubstituted sulfamoyl, cyano, nitro, optionally substituted aryl,optionally substituted aryloxy, optionally substituted arylthio,optionally substituted arylsulfinyl, optionally substitutedarylsulfonyl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy, optionallysubstituted heteroarylthio, optionally substituted heteroarylsulfinyl,optionally substituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy or an optionally substituted non-aromaticheterocyclic group; R⁹ is independently a halogen atom, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted alkyloxy, oxo, optionally substituted aryl, optionallysubstituted heteroaryl or an optionally substituted non-aromaticheterocyclic group; M is carbonyl or sulfonyl; Y is a single bond,optionally substituted alkylene optionally containing one or twoheteroatom(s), optionally substituted alkenylene optionally containingone or two heteroatom(s), optionally substituted alkynylene optionallycontaining one or two heteroatom(s), an oxygen atom, a sulfur atom or—N(R¹¹)—; L¹ and L² are independently a single bond, optionallysubstituted alkylene optionally containing one or two heteroatom(s),optionally substituted alkenylene optionally containing one or twoheteroatom(s), optionally substituted alkynylene optionally containingone or two heteroatom(s), or —N(R¹²)—; R¹¹ and R¹² are independently ahydrogen atoms, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcycloalkyl, acyl, optionally substituted alkyloxy, optionallysubstituted aryl, optionally substituted heteroaryl or an optionallysubstituted non-aromatic heterocyclic group; n is 0, 1 or 2; and q is 0,1, 2 or 3; or a pharmaceutically acceptable salt thereof.
 22. A compoundof the general formula (II):

wherein the ring C is a ring of the formula of

X⁵ is —N═; R¹, R², R³ and R⁴ are independently hydrogen atoms, a halogenatom, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkenyl, hydroxy, optionally substitutedalkyloxy, optionally substituted alkenyloxy, optionally substitutedalkynyloxy, optionally substituted cycloalkyloxy, optionally substitutedcycloalkenyloxy, mercapto, optionally substituted alkylthio, optionallysubstituted alkenylthio, optionally substituted alkynylthio, optionallysubstituted alkylsulfinyl, optionally substituted alkylsulfonyl,optionally substituted alkylsulfonyloxy, optionally substitutedcycloalkylthio, optionally substituted cycloalkylsulfinyl, optionallysubstituted cycloalkylsulfonyl, optionally substitutedcycloalkylsulfonyloxy, optionally substituted cycloalkenylthio,optionally substituted cycloalkenylsulfinyl, optionally substitutedcycloalkenylsulfonyl, optionally substituted cycloalkenylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted aryloxycarbonyl,optionally substituted carbamoyl, optionally substituted sulfamoyl,cyano, nitro, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted arylthio, optionally substitutedarylsulfinyl, optionally substituted arylsulfonyl, optionallysubstituted arylsulfonyloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroarylthio, optionally substituted heteroarylsulfinyl, optionallysubstituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy or an optionally substituted non-aromaticheterocyclic group; R⁹ is independently a halogen atom, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted alkyloxy, oxo, optionally substituted aryl, optionallysubstituted heteroaryl or an optionally substituted non-aromaticheterocyclic group; R¹⁰ is hydroxyalkyl, carboxy, alkyloxycarbonyl,optionally substituted carbamoyl or a carboxy equivalent; R¹³ isoptionally substituted C1-C6 alkyloxy, optionally substituted C2-C6alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionallysubstituted C1-C6 alkylthio, optionally substituted C2-C6 alkenylthio,optionally substituted C2-C6 alkynylthio, optionally substituted C3-C6cycloalkyloxy, optionally substituted C3-C6 cycloalkylthio, optionallysubstituted aryloxy or optionally substituted arylthio; R¹¹ is ahydrogen atom, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcycloalkyl, acyl, optionally substituted alkyloxy, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted non-aromatic heterocyclic group; R¹⁴ is independentlyhalogen atom, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted carbamoyl, optionallysubstituted sulfamoyl, cyano, nitro, optionally substituted aryl,optionally substituted arylsulfonyloxy, optionally substitutedheteroaryl or an optionally substituted non-aromatic heterocyclic group;M is carbonyl or sulfonyl; Z is CH, C(R¹⁴), or N; L³ is a single bond,optionally substituted alkylene optionally containing one or twoheteroatom(s), optionally substituted alkenylene optionally containingone or two heteroatom(s), optionally substituted alkynylene optionallycontaining one or two heteroatom(s), an oxygen atom, a sulfur atom or agroup of —N(R¹¹)—; n is 0, 1 or 2; and q is 0, 1, 2 or 3; or apharmaceutically acceptable salt thereof.
 23. A compound of claim 22wherein M is sulfonyl; or a pharmaceutically acceptable salt thereof.24. A compound of claim 22 wherein R¹⁰ is carboxy; or a pharmaceuticallyacceptable salt thereof.
 25. A compound of claim 22 wherein L³ isoptionally substituted alkylene; or a pharmaceutically acceptable saltthereof.
 26. A compound of claim 22, wherein one of R¹ to R⁴ is ahydrogen atom, a halogen atom, optionally substituted alkyl, optionallysubstituted alkyloxy, optionally substituted amino, optionallysubstituted carbamoyl, optionally substituted aryl, optionallysubstituted heteroaryl or an optionally substituted non-aromaticheterocyclic group, and others of R¹ to R⁴ are a hydrogen atom, ahalogen atom or optionally substituted alkyl; or a pharmaceuticallyacceptable salt thereof.
 27. A compound of claim 22 wherein R¹³ isoptionally substituted C1-C6 alkyloxy or optionally substituted C1-C6alkylthio; or a pharmaceutically acceptable salt thereof.
 28. A compoundof claim 22 wherein R¹⁴ is a halogen atom, optionally substituted alkylor optionally substituted alkyloxy; or a pharmaceutically acceptablesalt thereof.
 29. A compound of claim 22 wherein R⁹ is alkyl or oxo, andn is 0 or 1; or a pharmaceutically acceptable salt thereof.
 30. Apharmaceutical composition comprising the compound of claim 21, or apharmaceutically acceptable salt thereof as an active ingredient, and apharmaceutical additive.
 31. A pharmaceutical composition of claim 30which is a DP receptor antagonist.
 32. A pharmaceutical composition ofclaim 30 which is a therapeutic agent for allergy.
 33. A pharmaceuticalcomposition of claim 32 wherein the therapeutic agent for allergy is amedicine for asthma.
 34. A pharmaceutical composition comprising thecompound of claim 22, or a pharmaceutically acceptable salt thereof asan active ingredient, and a pharmaceutical additive.